Video
Autophagy - Macroautophagy \u0026 Importance in Health Thank you for visiting nature. Citrus supplement for inflammation are using a browser version with forkation support Autophagy and autolysosome formation Anv. To formatkon the best experience, autllysosome recommend you Antioxidants in human health a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Autophagy is a major intracellular degradation system that derives its degradative abilities from the lysosome. The most well-studied form of autophagy is macroautophagy, which delivers cytoplasmic material to lysosomes via the double-membraned autophagosome.Autophagy and autolysosome formation -
When ESCRT-mediated lysosome repair fails, galectin-3 recruits TRIM16 for removal of unsalvageable lysosomes by autophagy, aided by the autophagy-inducing effects of galectin-8 and galectin-9 Jia et al.
In this way, components of the endosomal system and the autophagy machinery are instrumental for the homeostasis of lysosomes. Autophagy and endocytosis mediate the degradation and recycling of intracellular and extracellular components, respectively.
Both pathways involve the gradual maturation and fusions of vesicles, which traffic to their final destination, the lysosome. The emerging extensive crosstalk between these two pathways is therefore not surprising.
Many questions regarding the identity and composition of various intracellular membrane compartments, as well as differential control of their intersections and the protein complexes involved still remain unanswered.
Novel high-resolution live-cell imaging approaches combined with proteomics and CRISPR-based screens will undoubtedly provide further insight. Elucidation of the dynamic interplay between autophagy and endocytosis in the regulation of cell signaling is likely to provide exciting avenues for development of new therapeutic approaches.
We thank members of the Molecular Cancer Research Group for important discussions and Trond Lamark for critical reading of the manuscript. Research in T. is supported by a grant from the Northern Norway Regional Health Authority Helse Nord RHF; grant number HNF We are now welcoming submissions for our upcoming Special Issue: Imaging Cell Architecture and Dynamics.
This issue will be coordinated by two Guest Editors: Lucy Collinson The Francis Crick Institute, UK and Guillaume Jacquemet University of Turku, Finland.
Submission deadline: 1 March People who know JCS well will know that we're more than just a journal and that our community — the cell biology community — really is at the heart of everything we do. Read the full Editorial by Editor-in-Chief Michael Way and Executive Editor Seema Grewal.
Registration is open for our Journal Meeting Diversity and Evolution in Cell Biology, which aims to bring together evolutionary biologists and cell biologists investigating diverse aspects of cellular physiology.
Submit your abstract by 5 April. Final registration deadline: 3 May Early-career researchers interested in the roles of nuclear lipids, apply now for one of the ten funded places at this Workshop, which will take place October Application deadline: 19 April.
There are many benefits to publishing in Journal of Cell Science - read more about why you should choose JCS or visit our submission page now. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.
filter your search All content All journals Journal of Cell Science. Advanced Search. User Tools Dropdown. Sign in. Toggle Menu Menu Articles Accepted manuscripts Latest complete issue Issue archive Archive by article type Special issues Subject collections Interviews Essay series Sign up for alerts About us About JCS Editors and Board Editor biographies Travelling Fellowships Grants and funding Journal Meetings Workshops The Company of Biologists The Forest of Biologists Journal news For authors Submit a manuscript Aims and scope Presubmission enquiries Fast-track manuscripts Article types Manuscript preparation Cover suggestions Editorial process Promoting your paper Open Access JCS Prize Manuscript transfer network Biology Open transfer Journal info Journal policies Rights and permissions Media policies Reviewer guide Sign up for alerts For librarians Contacts Contacts Subscriptions Advertising Feedback.
Skip Nav Destination Close navigation menu Article navigation. Volume , Issue Previous Article Next Article. Article contents. Overview of the autophagy pathway.
Overview of endocytosis. Impact of autophagy on endocytosis and signaling. Autophagosome formation and its intersection with the endosomal system. Autophagosome maturation is dependent on fusion with the endolysosomal system. Vesicle transport governs fusion between autophagosomes and the endolysosomal system.
Lysosome quality control. Conclusions and perspectives. Article Navigation. REVIEW 22 May Autophagy and endocytosis — interconnections and interdependencies In collection: Autophagy , Membrane Trafficking.
Birgisdottir birgisdottir uit. no ; terje. johansen uit. This site. Google Scholar. Terje Johansen Author and article information. Competing interests The authors declare no competing or financial interests. Online ISSN: Norges Forskningsråd Kreftforeningen Helse Nord RHF HNF Published by The Company of Biologists Ltd.
J Cell Sci 10 : jcs Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide. Table 1. View Large. Box 1.
LC3-associated phagocytosis and LAP-like processes. Box 2. Nutrient sensing and mTORC1 regulation to maintain lysosome homeostasis and autophagic flux. Funding Research in T.
Search ADS. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum.
Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs.
Endolysosomes are the principal intracellular sites of acid hydrolase activity. Beyond self-eating: the control of nonautophagic functions and signaling pathways by autophagy-related proteins. TRIMs and galectins globally cooperate and TRIM16 and galectin-3 co-direct autophagy in endomembrane damage homeostasis.
A mammalian autophagosome maturation mechanism mediated by TECPR1 and the AtgAtg5 conjugate. Pacer mediates the function of class III PI3K and HOPS complexes in autophagosome maturation by engaging Stx Cellular functions and molecular mechanisms of the ESCRT membrane-scission machinery.
Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. To degrade or not to degrade: mechanisms and significance of endocytic recycling. De Duve. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes.
RAB2 regulates the formation of autophagosome and autolysosome in mammalian cells. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting AtgL1. The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes.
Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling. LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy.
A syntaxin SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells.
Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNAREs. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance.
LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer's disease. A novel AAK1 splice variant functions at multiple steps of the endocytic pathway. LC3-associated phagocytosis - the highway to hell for phagocytosed microbes.
Nutrient-dependent mTORC1 association with the ULK1-AtgFIP complex required for autophagy. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover.
Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy.
Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion.
Galectin-3 coordinates a cellular system for lysosomal repair and removal. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors.
ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ. Small GTPase Rab1B is associated with ATG9A vesicles and regulates autophagosome formation.
Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases. Beyond starvation: an update on the autophagic machinery and its functions. Beclininteracting autophagy protein Atg14L targets the SNARE-associated protein Snapin to coordinate endocytic trafficking.
Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA A receptors.
Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation. Rab7 knockout unveils regulated autolysosome maturation induced by glutamine starvation. Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins.
Influenza A virus NS1 protein suppresses JNK1-dependent autophagosome formation mediated by Rab11a recycling endosomes. Watch what you Self- eat: autophagic mechanisms that modulate metabolism. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking.
Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. Microtubule-associated protein 1 light chain 3 alpha LC3 -associated phagocytosis is required for the efficient clearance of dead cells.
Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation.
Autophagosomal YKT6 is required for fusion with lysosomes independently of syntaxin Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.
Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. Identification of clathrin heavy chain as a direct interaction partner for the γ-aminobutyric acid type A receptor associated protein. Rab4 function in membrane recycling from early endosomes depends on a membrane to cytoplasm cycle.
mTOR activates the VPSUVRAG complex to regulate autolysosomal tubulation and cell survival. Phosphatidylinositolphosphate in the regulation of autophagy membrane dynamics. The enigmatic endosome - sorting the ins and outs of endocytic trafficking.
Autophagy in the context of the cellular membrane-trafficking system: the enigma of Atg9 vesicles. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport.
Detection and clearance of damaged lysosomes by the endo-lysosomal damage response and lysophagy. Rab GTPases: master regulators that establish the secretory and endocytic pathways.
TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers.
Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. A Ragulator-BORC interaction controls lysosome positioning in response to amino acid availability.
The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A.
ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. Plasma membrane contributes to the formation of pre-autophagosomal structures.
Rab conversion as a mechanism of progression from early to late endosomes. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p Glued and late endosome positioning.
Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation.
Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation. Autophagy-dependent shuttling of TBC1D5 controls plasma membrane translocation of GLUT1 and glucose uptake. A VPS33A-binding motif on syntaxin 17 controls autophagy completion in mammalian cells. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis.
Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin The role of molecular chaperones in clathrin mediated vesicular trafficking.
This is the end: regulation of Rab7 nucleotide binding in endolysosomal trafficking and autophagy. Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy.
The BifDynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rabpositive reservoirs.
An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure. Chaperone-mediated autophagy and endosomal microautophagy: jointed by a chaperone.
A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.
The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. However, not all autophagy signals are transduced through mTOR; some amino acid signaling can suppress autophagy in an mTOR-independent manner Mordier et al. More recently, small-molecule enhancers of the cytostatic effects of rapamycin called SMERs were identified to induce autophagy, which acts independently of mTOR Sarkar et al.
In addition to insulin and amino acid signaling, the involvement of many other factors in autophagy regulation has recently been reported Codogno and Meijer These include Bcl-2 see below , reactive oxygen species ROS Djavaheri-Mergny et al. Membrane dynamics during autophagy are highly conserved from yeast to plants and animals.
In the first step of autophagosome formation, cytoplasmic constituents, including organelles, are sequestered by a unique membrane called the phagophore or isolation membrane, which is a very flat organelle like a Golgi cisterna.
Complete sequestration by the elongating phagophore results in formation of the autophagosome, which is typically a double-membraned organelle. This step is a simple sequestration, and no degradation occurs.
Where and how autophagosomes emerge has been a major question. In yeast, 31 Atg autophagy-related proteins have been identified, and many of them gather at a site that can be identified by fluorescence microscopy as a punctate spot very close to the vacuolar membrane. Unfortunately, detailed structural information regarding the PAS is not currently available, and it is even unknown whether it is a membranous structure.
Equivalent structures have not been observed in mammalian cells. Yeast cells may have a stable PAS because it is shared with the cytoplasm-to-vacuole targeting Cvt pathway, a constitutive transport pathway for amino peptidase 1 Ape1 and α-mannosidase Ams1 from the cytosol to the vacuole Klionsky and Ohsumi Since the function of these Atg proteins has been extensively reviewed Klionsky ; Klionsky et al.
A recent systematic analysis showed that the AP-Atg proteins depend on each other for recruitment to the PAS Suzuki et al. The recently identified Atg29 Kawamata et al.
Atg11 is also important for PAS organization but is essential only for the Cvt pathway Suzuki et al. Other AP-Atg proteins target to the PAS as shown in Figure 2 and exert their own roles in autophagosome formation.
Although the precise function of each protein remains to be understood, an unexpected function was shown for yeast Atg8. Atg8, a ubiquitin-like protein, is present on autophagic membranes as a phosphatidylethanolamine PE -conjugated form Atg8-PE. Atg8 mediates tethering and hemifusion of liposomes containing Atg8-PE in an in vitro system Nakatogawa et al.
Interdependence of Atg proteins for PAS localization. This figure is based on the hierarchical classification analysis performed in yeast by Suzuki et al. Blue arrows indicate interdependence of Atg proteins for PAS targeting. For example, PAS-targeting of Atg5 is highly dependent on the class III PI3-kinase complex, but not on Atg8 or Atg2.
Black arrows indicate positive and negative regulation. Some mammalian-specific proteins Bcl-2, Bcl-X L , UVRAG, and Ambra1 are listed, but PAS targeting has not been determined because a PAS-equivalent structure has not been identified in mammalian cells.
Parentheses indicate mammalian nomenclature. Although many Atg proteins are conserved between yeast and mammals, several mammalian-specific factors that modulate the functions of Atg proteins have been identified.
Beclin 1 was originally identified as an interaction partner of Bcl-2, an anti-apoptotic protein Liang et al. This Bcl-2—Beclin 1 interaction is mediated through a BH3 domain in Beclin 1 Maiuri et al.
The endoplasmic reticulum ER -targeted but not mitochondrial-targeted Bcl-2 effectively suppresses autophagy Pattingre et al. The starvation-induced dissociation of Beclin 1 and Bcl-2 or Bcl-X L could be one manner in which nutrient starvation induces autophagy. Therefore, it was proposed that Bcl-2 is not only an anti-apoptotic but also an anti-autophagic protein.
Alternatively, Bcl-2 was reported to suppress autophagy by inhibiting cytosolic calcium elevation, which can induce autophagy Hoyer-Hansen et al. Another Beclin 1 partner is UVRAG UV irradiation resistance-associated gene Liang et al.
UVRAG was shown to be a member of the class III PI3-kinase complex and a positive regulator of autophagy.
Most recently, a WD domain-containing protein named Ambra1, which was identified by a gene trap experiment, was shown to be a Beclin 1-interacting protein Maria Fimia et al. Ambra1 is primarily expressed in neural tissues and is indispensable for normal neural tube development.
Therefore, mammalian Beclin 1 is likely to be regulated by its binding partners, which may not be present in yeast. Considering that Beclin 1 knockout mice die at about embryonic day 7.
Characterization of its interacting proteins will facilitate our understanding of the role of Beclin 1 in autophagy and possibly other pathways. Autophagosome membranes cannot recognize what they enclose, as most of their contents are not proximal to the autophagosomal membrane.
Therefore, sequestration takes place primarily in a random manner. However, autophagosome membranes can recognize some proteins, and possibly organelles, at their surfaces. The best-studied example of such selective incorporation is the Cvt pathway Klionsky and Ohsumi ; Klionsky This differs somewhat from canonical autophagy, as Cvt vesicles are much smaller than autophagosomes.
However, as the membrane dynamics and molecular machinery of the Cvt pathway are quite similar to those of autophagy, the Cvt pathway may be thought of as selective autophagy of the vacuolar enzymes Ape1 and Ams1 although these enzymes are not targeted for degradation.
In this case, Atg19 functions as a cargo receptor for selective incorporation of these enzymes into Cvt vesicles Klionsky Some Cvt-specific factors are also used for selective degradation of peroxisomes in Pichia pastoris Klionsky et al.
One way selective autophagy can be achieved is through the specific protein composition of the autophagosome membrane. The compositions of the outer and inner autophagosomal membranes seem to be quite different.
To date, only LC3, a mammalian homolog of Atg8, has been identified on the autophagosomal inner membrane Kabeya et al. Although the precise mechanism is not known, preferential degradation by autophagy also has been demonstrated for Ald6 in yeast Onodera and Ohsumi , peroxisomes and catalase Luiken et al.
There should be various mechanisms underling selective autophagy, which remain to be revealed. In the next step, autophagosomes fuse with lysosomes in metazoan cells or vacuoles in yeast and plant cells. In addition, it has been proposed that autophagosomes fuse with endosomes to become amphisomes before fusion with lysosomes Tooze et al.
Fusion with endosomes is believed to provide nascent autophagosomes with machinery that is required for lysosome fusion. The definition of autophagosomes, amphisomes, and autolysosomes is based on their function, not on morphology Fig. Therefore, it is not always easy to distinguish these structures by electron microscopy.
One current problem is that this degradation step is rather difficult to measure, although some methods to monitor autophagy flux have been proposed Tanida et al. However, little is known about this step. Yeast Atg22, which was first identified as Aut4, a membrane protein required for the breakdown of autophagic bodies Suriapranata et al.
The contribution of autophagy to reuse of other macromolecules such as carbohydrates and lipids is unknown. In this section, the physiological roles of autophagy are discussed based on the aforementioned processes Fig.
Under normal conditions and during very short periods of starvation, maintenance of the amino acid pool seems to rely primarily on the ubiquitin—proteasome system rather than autophagy Vabulas and Hartl However, during starvation that persists for several hours, necessary amino acids are produced by autophagy, which is up-regulated as an adaptive response.
Indeed, both intracellular and extracellular amino acid levels decrease in autophagy-deficient yeast cells Onodera and Ohsumi and mice Kuma et al.
Although induction of autophagy is critical for survival of starvation, it is not fully understood how the generated amino acids are used. At least three pathways are likely to exist.
First, in animals, carbohydrate stores i. Thereafter, glucose is supplied through gluconeogenesis in the liver; this process uses lactate and amino acids. In the well-described glucose—alanine cycle, alanine is secreted from peripheral tissues, including muscle, and is delivered to the liver to be converted to glucose during starvation.
Autophagy may be a major contributor to this cycle. Second, amino acids can be used as an energy source through the tricarboxylic acid TCA cycle. It is generally believed that both glucose and amino acids are important for energy homeostasis and cell proliferation Newsholme et al.
Recent studies have suggested that energy can be produced through autophagy. One study demonstrated that autophagy could support viability of an ILdependent hematopoietic cell line established from apoptosis-deficient mice even after IL-3 withdrawal. However, when autophagy was also suppressed, cell viability could be restored by addition of methylpyruvate, which is cell permeable and can serve as a substrate of the TCA cycle Lum et al.
Another recent study demonstrated that autophagy-defective embryoid body cells differentiated from embryonic stem cells undergoing apoptosis fail to expose phosphatidylserine at the cell surface due to low levels of cellular ATP, which can be overcome by addition of methylpyruvate Qu et al.
Third, amino acids produced by autophagy can be used to synthesize proteins, which are important for adaptation to starvation environments.
Yeast cells decrease bulk protein synthesis during starvation, but the reduction is much more severe in autophagy-defective mutant cells Onodera and Ohsumi In addition, up-regulation of several starvation-induced proteins, including argininosuccinate synthetase Arg1 , heat shock protein of 26 kDa Hsp26 , Ape1, and carboxypeptidase Y CPY , occurs only slightly in autophagy mutants during nitrogen starvation.
Inefficient production of such adaptive proteins may be a primary cause of loss of viability during starvation in autophagy-deficient cells Tsukada and Ohsumi More dynamic nutrient mobilization via autophagy appears to be observed in remodeling during development.
It should be noted that most remodeling steps are related to nutrient starvation, which can facilitate autophagy.
These processes include spore formation in yeast Tsukada and Ohsumi , multicellular development fruiting body formation of Dictyostelium discoideum Otto et al. Indeed, autophagy-defective mutants do not succeed in these remodeling processes, probably due to shortage of amino acids, which cannot be obtained from the environment during these periods.
These three usages are not mutually exclusive. Cells or organisms probably combine more than one function to survive adverse conditions Tsukada and Ohsumi ; Otto et al.
In addition to nutrient limitation, it has been suggested that autophagy might be responsive to hypoxia: Autophagy is induced in a mouse cerebral ischemia-hypoxia model Adhami et al. This might be mediated by HIF-1, a master regulator of the hypoxic response Bohensky et al.
Such metabolic stress typically induces apoptosis, but apoptosis-defective cells can survive under hypoxic conditions. Since cell survival depends on autophagy, excess amino acid generation is likely important under conditions of metabolic stress.
If both apoptosis and autophagy are suppressed, cell survival is severely impaired. Intriguingly, the resulting necrotic cell death promotes tumorigenesis, which is probably mediated by the inflammatory response Degenhardt et al.
Thus, tumorigenesis may be a secondary effect of autophagy suppression in this context further discussed below. It should be emphasized that excess production of amino acids by autophagy is an acute response or emergency action. Therefore, induction of autophagy can support cell survival only for a short time.
For example, during tumor growth, autophagy is activated at initial stages, but returns to basal levels after a blood supply is established Degenhardt et al.
In contrast, little is known about how useful autophagy is in overcoming chronic starvation. The second purpose of autophagy is the elimination of cytoplasmic contents. The most direct evidence is the accumulation of abnormal proteins and organelles in autophagy-deficient hepatocytes, neurons, and cardiomyocytes even in the absence of any disease-associated mutant protein Komatsu et al.
Soluble ubiquitinated proteins, ubiquitin-positive inclusion bodies, and deformed organelles accumulate in these cells. Since induced autophagy is not observed in the brain during starvation, low levels of basal autophagy are likely sufficient for quality control.
Some types of induced autophagy are aimed at the elimination of excess or unneeded organelles. For example, peroxisomes induced by metabolic demand are selectively degraded primarily by microautophagy Sakai et al. Similarly, damaged mitochondria seem to be selectively eliminated by macroautophagy, while mitophagy occurs nonselectively under starvation conditions Kim et al.
The elimination of cytoplasmic contents by autophagy is so important that defects cause various cellular malfunctions. Two possible outcomes of autophagy defects, neurodegeneration and tumorigenesis, are discussed further. It remains largely unknown whether these represent up-regulation of autophagy or blockage of autophagic flux.
Since neural tissue-specific knockout of autophagy genes causes neurodegenerative disease, and there are many reports showing that degradation of various disease-associated mutant proteins largely depends on autophagy Rubinsztein ; Martinez-Vicente and Cuervo , one would expect up-regulation of autophagic activity to be a useful therapeutic strategy for treatment of such disorders.
Indeed, rapamycin and its analog CCI, which induce autophagy by inhibiting TOR, attenuate symptoms in fly and mouse Huntington disease models Ravikumar et al. Furthermore, the autophagy-enhancing SMERs, which function independently of mTOR suppression, accelerate the clearance of mutant huntingtin and α-synuclein and protect against neurodegeneration in a fly Huntington disease model Sarkar et al.
Whether abnormal proteins and inclusion bodies are selectively degraded by autophagy in these cases remains unknown; the random degradation of cytoplasmic contents may fully account for the effects of these autophagy inducers.
However, as discussed above, pmediated recognition of ubiquitinated proteins and inclusion bodies was proposed Bjørkøy et al. p62 gene-targeting experiments should further clarify the contribution of this type of selective autophagy. Another possible outcome of defects in autophagic degradation is tumorigenesis.
Although autophagy may be a survival mechanism for tumor cells Lum et al. Monoallelic deletions of Beclin 1 are frequently observed in human breast, ovarian, and prostate cancers Liang et al. Allelic loss of beclin1 in immortal kidney and mammary epithelial cells promotes tumorigenesis Karantza-Wadsworth et al.
Like Beclin 1, UVRAG is mutated in human cancers Ionov et al. The expression of UVRAG suppresses anchorage-independent growth of HCT cells human colon cancer cells with a UVRAG mutation , while a dominant-negative form of UVRAG promotes cell growth Liang et al.
Atg4C knockout mice show an increased susceptibility to carcinogen-induced fibrosarcomas Marino et al. How autophagy protects against tumorigenesis is not fully understood.
As discussed above, it was proposed that loss of autophagy causes necrotic cell death in apoptosis-deficient cells during metabolic stress; this might contribute to tumorigenesis via the inflammatory response Degenhardt et al. However, it was also suggested that loss of autophagy in these cells has a cell-autonomous effect on tumorigenesis; autophagy can limit genome damage Karantza-Wadsworth et al.
Furthermore, DNA damage and genomic instability were demonstrated in mammary epithelial cells in response to metabolic stress when both autophagy and apoptosis were suppressed Karantza-Wadsworth et al. This genome damage and genetic instability promoted by defective autophagy may drive tumor progression by elevating the mutation rate.
It may be that autophagy prevents the accumulation of abnormal proteins and organelles that are harmful to genomic stability; for example, as described above, damaged mitochondria can be selectively degraded by autophagy Kim et al.
Consistent with this, mitochondria with abnormal shape are found in Atg7-deficient hepatocytes Komatsu et al. Even in yeast, autophagy was found to be important for maintaining mitochondrial function Zhang et al.
Importantly, ROS accumulate in autophagy-defective yeast mutants when they are cultured in nonfermentable medium.
Autophagy-defective plants also show increased oxidative stress under normal conditions Xiong et al. These ROS may promote DNA damage and ultimately tumorigenesis.
Elimination by autophagy is directed not only at cellular self-components, but also intracellular pathogens. Various pathogenic bacteria, such as Streptococcus pyogenes Nakagawa et al. Another well-known pathogen persisting inside phagocytes is Mycobacterium tuberculosis.
These bacteria inhibit phagosome maturation and survive in premature phagosomes. However, when autophagy is stimulated by starvation, rapamycin, or IFN-γ, mycobacterial phagosomes are enclosed, delivered to lysosomes, and acidified, which results in microbacterial death Gutierrez et al.
IFN-γ-induced autophagy in mouse cells requires a downstream effector, Irgm1 LRG , which is an immunity-related guanosine triphosphatase IRG Singh et al.
In contrast to mouse cells, human IRGM is not induced by IFN-γ, but it was suggested that constitutive expression of IRGM could mediate autophagy in human macrophages Singh et al. Atg16L is one of two Atg16 homologs and interacts with the Atg12—Atg5 conjugate that is essential for autophagosome formation Mizushima et al.
It is also possible that excessive degradation by autophagy causes cell death. However, there is almost no evidence supporting this speculation under physiological or pathological conditions Edinger and Thompson ; Debnath et al.
During development, autophagy occurs in dying cells in various embryonic tissues Levine and Klionsky ; Mizushima However, such autophagy can be interpreted as a nutrient mobilization system.
It remains unknown whether these cells would survive if autophagy were blocked. At times, autophagy can be simply used as a pathway from the cytosol to lysosomes or vacuoles. The clearest example is the Cvt pathway in yeast.
The vacuolar enzymes, Ape1 and Ams1, are synthesized without signal sequences and are cytosolic. They are delivered to the vacuole, where they function, by the autophagy-related Cvt pathway Klionsky This is apparently a biosynthetic rather than a degradation pathway.
In the case of MHC class I antigen presentation, the proteasome degrades endogenous antigens into peptides, which are then delivered to the ER lumen via the transporter associated with antigen processing TAP.
In contrast, the antigen-binding site of MHC class II molecules is blocked by the invariant chain until they reach the MHC class II loading compartment MIIC , which is related to the lysosome.
Therefore, endogenous peptides cannot bind MHC class II in the ER, allowing exogenous peptides to efficiently bind MHC class II following endocytosis. Recent evidence suggests that autophagy both macroautophagy and CMA accounts for the delivery of these peptides Schmid and Münz Small molecules can activate TFEB indirectly by modulating its upstream kinases or phosphatases Table 1.
For example, TFEB nuclear transport is promoted by rapamycin via inhibiting mTORC1 activity or by compounds isolated from the herb Euphorbia peplus Linn via the PKC—GSK3β cascade Chloroquine CQ , hydroxychloroquine HCQ and their derivatives are the only clinically approved drugs that act on autophagosome maturation Table 1.
They are used alone or in combination with other drugs, mostly in ongoing oncology trials, in general with the goal of optimizing therapies by blocking autophagy induced by cancer treatments , , The new-generation dimeric CQ derivatives Ly05 and DQ are active at lower concentrations than CQ and HCQ , , CQ and HCQ block autophagy flux by inhibiting the hydrolytic capacity of autolysosomes.
They increase the pH in autolysosomal compartments and hence block the activity of acidic proteases and other enzymes Thus, inhibition of PPT1 results in autophagy inhibition. Of note, lysosomotropic agents target all acidic compartments and also other pathways , , and thus in some cases the beneficial effects of lysosomotropic agents can be attributed to mechanisms other than a blockade of autophagy , For example, these drugs inhibit tumour progression, independently of the autophagy blockade, by altering the trafficking of signalling molecules that is, NOTCH1 in the endocytic pathway and by other mechanisms , It is also worth mentioning that the activity of CQ and HCQ observed in vitro may not be the same in vivo due to different parameters.
Moreover, the acidic environment in tumours can protonate the lysosomotropic agent and greatly reduce its cellular uptake Autophagosome maturation is an essential step in the autophagy pathway that ensures the formation of degradative autolysosomes.
It adds another layer of complexity and provides an extra node to integrate nutrient status and stresses for regulation of autophagic degradation.
The distinct organization and trafficking of the endolysosomal compartment in different cell types and growth conditions add complexity at the intersection of the autophagy and endocytic pathways. Thus, the trans -SNARE complexes and tethering factors act coordinately with context-specific factors to mediate fusion of autophagosomes with endocytic vesicles and lysosomes.
Further investigations are needed to elucidate how different signalling pathways and stresses coordinate autophagosome initiation and maturation to ensure efficient progression of autophagic flux and how these processes are adapted in different cell types or pathophysiological contexts.
Autophagosome maturation is widely manipulated by pathogens to escape from destruction and for replication and growth. Pathogens that use autophagic vacuoles for replication can both activate autophagosome initiation and block maturation to achieve their maximal accumulation.
Understanding how viral proteins and bacterial virulence factors modulate host autophagy will help us to develop strategies to interfere with the pathogen—host interaction and even to restore autophagy as a defence mechanism.
Such strategies are urgently required with the evolution of multidrug-resistant bacteria. Elucidating the underlying mechanisms for autophagosome maturation defects and deregulation of the function of the autophagosome—lysosome system is also key for us to understand the pathogenesis of various human diseases.
Targeting autophagosome maturation — via modulation of SNAREs, tethers and their regulators as well as lysosome biogenesis and function — offers an effective strategy for the treatment of these diseases. Biomarkers and methods that reliably monitor autophagy flux in vivo are needed to examine temporal changes of autophagy activity and to evaluate interventions that target autophagosome maturation.
A combination of assays has been used to measure autophagy flux and to monitor autophagosome maturation However, many of these assays are difficult to implement in humans. Several methods have recently been developed to serve as reliable autophagy biomarkers in humans Analysis of autophagy flux in isolated peripheral blood mononuclear cells is used to measure autophagy activity in human blood samples , Positron emission tomography can be used with hypoxia tracers to correlate hypoxia and autophagy in tumours and also to gauge the level of specific autophagy substrates in tissues by the use of positron emission tomography ligands that bind to autophagy substrates , The levels of specific molecules in biological fluids can also be used to determine autophagy flux in tissues.
For instance, the blood level of arginase 1 reflects autophagy activity in the liver Thus, to screen drugs targeting autophagy, there is an urgent need for reliable, high-throughput clinical biomarkers to measure autophagic activity by the identification of tissue-specific circulating autophagy by-products and the development of flux probes for use in imaging techniques.
Feng, Y. The machinery of macroautophagy. Cell Res. Article CAS PubMed Google Scholar. Lamb, C. The autophagosome: origins unknown, biogenesis complex. Cell Biol. Nakatogawa, H. Mechanisms governing autophagosome biogenesis. Mizushima, N.
The role of Atg proteins in autophagosome formation. Cell Dev. Stolz, A. Cargo recognition and trafficking in selective autophagy. Takahashi, Y. et al. An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure. Article PubMed PubMed Central CAS Google Scholar.
VPS37A directs ESCRT recruitment for phagophore closure. Article CAS PubMed PubMed Central Google Scholar. Zhen, Y. ESCRT-mediated phagophore sealing during mitophagy. Autophagy 16 , — Ktistakis, N.
Digesting the expanding mechanisms of autophagy. Trends Cell Biol. Zhao, Y. Formation and maturation of autophagosomes in higher eukaryotes: a social network. Autophagosome maturation: an epic journey from the ER to lysosomes. Pu, J. Mechanisms and functions of lysosome positioning.
Cell Sci. CAS PubMed PubMed Central Google Scholar. Jiang, P. Autophagy and human diseases. Choi, Y. Autophagy during viral infection — a double-edged sword.
Deretic, V. Autophagy in infection, inflammation and immunity. Kimmey, J. Bacterial pathogens versus autophagy: implications for therapeutic interventions. Trends Mol. Levine, B. Autophagy in immunity and inflammation. Nature , — Filimonenko, M. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease.
Razi, M. Early endosomes and endosomal coatomer are required for autophagy. Jahn, R. SNAREs — engines for membrane fusion.
Langemeyer, L. Rab GTPase function in endosome and lysosome biogenesis. Yu, I. Tethering factors as organizers of intracellular vesicular traffic. Nguyen, T. Vaites, L. Ji, C. β-Propeller proteins WDR45 and WDR45B control autophagosome maturation into autolysosomes in neural cells.
e6 Itakura, E. Cell , — Matsui, T. Autophagosomal YKT6 is required for fusion with lysosomes independently of syntaxin Takats, S. Autophagosomal syntaxin dependent lysosomal degradation maintains neuronal function in Drosophila.
Tsuboyama, K. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science , — Kumar, S. Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins.
Diao, J. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Miao, G. ORF3a of the COVID virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation.
Cell 56 , — e Interaction of the HOPS complex with syntaxin 17 mediates autophagosome clearance in Drosophila. Cell 25 , — Article PubMed PubMed Central Google Scholar. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin Stroupe, C.
Purification of active HOPS complex reveals its affinities for phosphoinositides and the SNARE Vam7p. EMBO J. Gao, J. Molecular mechanism to target the endosomal Mon1-Ccz1 GEF complex to the pre-autophagosomal structure. eLife 7 , e Hegedus, K.
The Ccz1-Mon1-Rab7 module and Rab5 control distinct steps of autophagy. Cell 27 , — Manil-Segalen, M. The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS Cell 30 , — Article CAS Google Scholar.
Tian, Y. elegans screen identifies autophagy genes specific to multicellular organisms. Wang, Z. Cell 63 , — Zhao, H. Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration. McEwan, D. Cell 57 , 39—54 The authors demonstrate that PLEKHM1 tethers autophagosomes and lysosomes by simultaneously binding to autophagosomal LC3 and lysosome-localized RAB7, and also promotes autophagosome—lysosome fusion by recruiting the HOPS complex.
Wijdeven, R. Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway. Wetzel, L. TECPR1 promotes aggrephagy by direct recruitment of LC3C autophagosomes to lysosomes. Chen, D. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the AtgAtg5 conjugate.
Cell 45 , — Jahreiss, L. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9 , — Korolchuk, V.
Lysosomal positioning coordinates cellular nutrient responses. Bonifacino, J. Moving and positioning the endolysosomal system. Jia, R. BORC coordinates encounter and fusion of lysosomes with autophagosomes. Autophagy 13 , — Pankiv, S. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport.
Johansson, M. Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-pGlued, ORP1L, and the receptor betalll spectrin.
Rocha, N. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p Glued and late endosome positioning. van der Kant, R. Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L.
PubMed Google Scholar. Lee, S. Maday, S. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. This work reveals that in primary neurons, autophagosomes formed at the distal tip of the axon undergo retrograde transport to the cell soma, accompanied by gradual maturation and acidification.
Fu, M. LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes. Cell 29 , — Cason, S. Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway. Article Google Scholar.
Russell, R. Autophagy regulation by nutrient signaling. Furuya, T. Negative regulation of Vps34 by Cdk mediated phosphorylation. Cell 38 , — Nazio, F. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6.
Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. Liu, C. Cul3-KLHL20 ubiquitin ligase governs the turnover of ULK1 and VPS34 complexes to control autophagy termination. Cell 61 , 84—97 Jean, S. Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion.
EMBO Rep. Fraldi, A. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. Shen, Q. Acetylation of STX17 syntaxin 17 controls autophagosome maturation. Autophagy 17 , — Guo, B. O-GlcNAc-modification of SNAP regulates autophagosome maturation.
Hanover, J. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Acta , 80—95 A brief history of autophagy from cell biology to physiology and disease. Funderburk, S. The beclin 1-VPS34 complex — at the crossroads of autophagy and beyond.
Matsunaga, K. Two beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages.
Cheng, X. Pacer mediates the function of class III PI3K and HOPS complexes in autophagosome maturation by engaging Stx Cell 65 , — Liang, C. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking.
Sun, Q. Rubicon controls endosome maturation as a Rab7 effector. Natl Acad. USA , — Zhong, Y. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with beclin 1-phosphatidylinositolkinase complex. Kim, Y. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation.
Cell 57 , — Judith, D. ATG9A shapes the forming autophagosome through arfaptin 2 and phosphatidylinositol 4-kinase III beta. Wang, H. GABARAPs regulate PI4P-dependent autophagosome: lysosome fusion. Del Bel, L.
Sac1, a lipid phosphatase at the interface of vesicular and nonvesicular transport. Traffic 19 , — Article PubMed CAS Google Scholar.
Cell 77 , — e5 Jaber, N. Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus. Carroll, B. Cell 25 , 15—28 Piper, R. Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2 , — Baba, T. Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome-lysosome fusion.
Raben, N. TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Sardiello, M. A gene network regulating lysosomal biogenesis and function. Settembre, C.
TFEB links autophagy to lysosomal biogenesis. Ballabio, A. Lysosomes as dynamic regulators of cell and organismal homeostasis. Puertollano, R. The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.
Li, Y. Protein kinase C controls lysosome biogenesis independently of mTORC1. Medina, D. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.
This study shows that upon activation by lysosomal calcium release through MCOLN1, the phosphatase calcineurin dephosphorylates TFEB and promotes its nuclear translocation to induce autophagy and lysosomal biogenesis.
Martina, J. Protein phosphatase 2A stimulates activation of TFEB and TFE3 transcription factors in response to oxidative stress. Banani, S. Biomolecular condensates: organizers of cellular biochemistry. Shin, Y. Liquid phase condensation in cell physiology and disease. Science , eaaf Zhang, H.
Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases. China Life Sci 63 , — Article PubMed Google Scholar. Boija, A. Transcription factors activate genes through the phase-separation capacity of their activation domains.
Sabari, B. Biomolecular condensates and gene activation in development and disease. Cell 55 , 84—96 Inositol polyphosphate multikinase inhibits liquid-liquid phase separation of TFEB to negatively regulate autophagy activity. Cell 55 , — This study demonstrates that the TFEB condensate formed via LLPS is involved in transcription and its formation is negatively regulated by the nuclear-localized protein IPMK.
Tabata, K. Fujita, N. Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.
eLife 6 , e The RBGRBG-2 complex modulates autophagy activity by regulating lysosomal biogenesis and function in C. Nixon, R. Neurodegenerative lysosomal disorders: a continuum from development to late age.
Autophagy 4 , — Otomo, A. Dysregulation of the autophagy-endolysosomal system in amyotrophic lateral sclerosis and related motor neuron diseases. Puls, I. Mutant dynactin in motor neuron disease. Parkinson, N.
ALS phenotypes with mutations in CHMP2B charged multivesicular body protein 2B. Neurology 67 , — Mauvezin, C. Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. McBrayer, M. A block of autophagy in lysosomal storage disorders. Vergarajauregui, S.
Autophagic dysfunction in mucolipidosis type IV patients. Decressac, M. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. USA , E—E Cortes, C. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.
This work reveals that the polyglutamine-expanded androgen receptor physically binds to and inactivates TFEB, thereby impairing autophagy function and contributing to the pathogenesis of spinal and bulbar muscular atrophy.
Flavin, W. Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Impaired endo-lysosomal membrane integrity accelerates the seeding progression of alpha-synuclein aggregates. Google Scholar. Cullup, T. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.
Byrne, S. Vici syndrome: a review. Orphanet J. Rare Dis. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy 9 , — Haack, T. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.
Saitsu, H. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Autophagy 11 , — Suleiman, J.
WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome. Role of Wdr45b in maintaining neural autophagy and cognitive function. Jiao, J. Skeletal muscle autophagy and its role in sarcopenia and organismal aging.
Dowling, J. X-linked myopathy with excessive autophagy: a failure of self-eating. Myerowitz, R. Impaired autophagy: the collateral damage of lysosomal storage disorders. EBioMedicine 63 , Nishino, I. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy Danon disease.
Tanaka, Y. Accumulation of autophagic vacuoles and cardiomyopathy in LAMPdeficient mice. Saraste, A. No cardiomyopathy in X-linked myopathy with excessive autophagy. Tresse, E.
Autophagy 6 , — Ju, J. Valosin-containing protein VCP is required for autophagy and is disrupted in VCP disease.
Citrus supplement for inflammation Biology volume 9Article Auyophagy Citrus supplement for inflammation Cite this article. Autolusosome details. Autophagy mediates lysosomal degradation of cytosolic components. Recent work has associated autophagic dysfunction with pathologies, including cancer and cardiovascular disease. To date, the identification of clinically-applicable drugs that modulate autophagy has been hampered by the lack of standardized assays capable of precisely reporting autophagic activity.
Jetzt kann ich an der Diskussion nicht teilnehmen - es gibt keine freie Zeit. Ich werde frei sein - unbedingt werde ich die Meinung aussprechen.
Wacker, mir scheint es, es ist die prächtige Phrase