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Another possibility for determining the fate of ubiquitinated protein is the quality of ubiquitin chains. It is thought that Kubiquitinated proteins are degraded by proteasome, whereas K63 chain modified proteins are substrates of aggrephagy.

However, M1, K63, and K48 chains can all trigger phase separation in vitro via binding to p62, albeit with a lower efficiency than the K48 chain [ 61 , ]. Perhaps the nature of aggrephagy substrates do not have much difference from those of the proteasome substrates and, rather, the high concentration of ubiquitin chains determines the aggrephagy fate by favoring a pmediated phase separation [ ].

The most well-known neurodegenerative disease associated with defects in ubiquitin-mediated autophagy is PD, which is the second most common late-onset neurodegenerative disease resulted from the loss of dopaminergic neurons in the substantia nigra pars compacta.

Mutations in genes encoding either PINK1 or Parkin are associated with autosomal recessive forms of PD [ ]. Mice deficient in either Parkin or PINK1 exhibit mitochondrial impairments, but most of them cannot recapitulate the prime features of human PD, that is, loss of dopaminergic neurons [ , ].

A recent study generated by Parkin homozygous knockout in the background of mice with the expression of a proof-reading defective mtDNA polymerase called mutator mice.

The combination of Parkin knockout and mtDNA mutation leads to the loss of dopaminergic neurons selectively in the substantia nigra and motor defect [ ].

This genetic evidence, in conjunction with the mitochondrial dysfunction found in brain and other organs of PD patients [ ], point out the importance of mitophagy in PD etiology. A recent study uncovered a link of ubiquitin-mediated autophagy regulation to various polyQ diseases.

Ataxin 3 is a polyQ-containing DUB and its polyQ expansion is associated with SCA type 3, in which neurodegeneration occurs in the striatum and cerebellum [ ].

Interestingly, the normal function of ataxin 3 is to remove the polyubiquitin chain from Beclin-1, leading to its stabilization [ 38 ]. With this function, ataxin 3 is required for starvation-induced autophagy. Importantly, several proteins with expanded polyQ repeats, including ataxin 3 itself, can compete with ataxin 3 for binding Beclin-1, in a polyQ length-dependent fashion.

Furthermore, although ataxin 3 with expanded polyQ repeats elicits higher binding affinity to Beclin-1, it is defective in removing ubiquitin chain from Beclin Thus, these findings identify a link of ataxin 3 to autophagy regulation and, more importantly, suggest that impairment of Beclinmediated autophagy accounts for one mechanism of polyQ repeat-associated neurodegenerative diseases.

As described above, ubiquitin serves as a tag to facilitate the autophagic degradation of intracellular pathogens xenophagy and a number of ubiquitin E3 ligases are involved in the addition of such tag.

Since autophagy core machinery is also required for the xenophagy process, regulators that affect ubiquitin-dependent turnover of autophagic core factors could also control xenophagy.

For instance, RNF, which targets Beclin-1 for ubiquitination and degradation, promotes Listeria monocytogenes proliferation and distribution in cell and mouse models [ 32 ].

Nevertheless, it should be noted that the bulk autophagy could elicit housekeeping function to restrict inflammation, thereby favoring pathogen survival [ 91 ]. The balance between selective autophagy and anti-inflammation could determine the outcome of infection and immunological functions.

One example for ubiquitination-mediated balance of anti-infection arm and anti-inflammation arm lies in USPdepedent Beclin-1 deubiquitination [ 39 ].

On one hand, this deubiquitination stabilizes Beclin-1 to favor autophagy-dependent pathogen clearance. On the other hand, the stabilized Beclin-1 binds to the CARD domain of MAVS to prevent MAVS-RIG-I association, thereby inhibiting type I interferon production and anti-viral immunity.

Autophagy is important in controlling hepatocyte lipid metabolism to maintain normal liver functions [ ]. Autophagy deficiency by ATG7 knockout aggravates liver steatosis induced by high fat diet and promotes the development of liver adenoma [ ].

Conversely, liver steatosis impairs autophagy through ATG7 downregulation [ ]. One important function of autophagy to regulate lipid metabolism is the turnover of lipid droplets via a selective autophagy process called lipophagy [ ].

Similar to other selective autophagy processes, lipophagy requires certain core autophagic factors. A recent study reveals an inhibitory role of HUWE1-mediated WIPI2 degradation in lipid droplet turnover in the liver, leading to the accumulation of liver neural lipids [ 48 ]. Besides liver disease, ubiquitin-mediated autophagy regulation is implicated in other metabolic syndromes.

For instance, failure of autophagy termination by KLHL20 deficiency potentiates muscle atrophy in diabetes mouse model [ 57 ]. Autophagy plays complex roles in cancer, which may depend on the different stages of cancer development. In the tumor initiating stage, autophagy suppresses carcinogenesis.

However, once tumor is formed, tumor cells exploit the autophagic process for them to survive in the harsh environments [ 17 ].

The impact of ubiquitin-mediated autophagy regulation on tumor formation and progression is poorly studied. A recent study reported that the Smurf1-induced UVRAG ubiquitination promotes not only autophagosome maturation but hepatocellular carcinoma HCC growth [ 56 ].

Furthermore, phosphorylation of UVRAG at S, which disrupts Smurf1 binding, correlates with poor survival of HCC patients. These findings support a tumor suppressive role of autophagy in HCC. In this review, we discussed the impact of protein ubiquitination in autophagy regulation.

The initiation and nucleation steps of autophagosome formation are most prevalently regulated by ubiquitination, meaning that ubiquitination controls the onset of autophagic process in response to various stressed conditions.

Nevertheless, later steps of autophagosome formation and autophagosome maturation are also subjected to ubiquitin-mediated regulation. Furthermore, ubiquitin-mediated protein turnover has been used as a prime mechanism for autophagy termination under prolonged stress conditions, thereby preventing the detrimental effect of excessive autophagic degradation.

The pleiotropic role of protein ubiquitination in autophagy regulation highlights the tight crosstalk between the two major cellular degradation machineries. Dysregulation of ubiquitin-mediated autophagy process has been implicated in many disease states, such as neurodegeneration, infectious diseases, liver diseases and metabolic syndromes.

With the important role of autophagy in maintaining normal physiology and homeostasis, it is expected to uncover further linkages between dysregulation of ubiquitin-mediated autophagy pathways and various human diseases, especially for age-related diseases.

In this regard, targeting of these pathways by modulating the activity of E3 ligase or DUB could be exploited as a strategy for disease intervention and has been an area receiving considerable attention. For example, the small molecular inhibitor of USP10 and USP13, called spautin-1, is capable of antagonizing the ubiquitination and degradation of Beclin-1 and p53, two tumor suppressor proteins, and therefore is a promising anti-cancer agent [ 37 ].

In the future, an improved understanding of how ubiquitin-mediated autophagy regulation contributes to the pathology of human diseases and the development of less toxic and more specific agents will benefit more patients.

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This work was supported by MOST Frontier Grant MOST—B and an intramural fund from Institute of Biological Chemistry, Academia Sinica. Academia Sinica, Institute of Biological Chemistry, Taipei, , Taiwan. Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, , Taiwan.

You can also search for this author in PubMed Google Scholar. All authors collected and reviewed literatures and wrote the manuscript. Y-H C and T-Y H designed and illustrated figures. All authors read and approved the final manuscript.

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Autophagy and the Red pepper shrimp degradagion UPS Autophagy and proteasomal degradation the two major intracellular protezsomal control and recycling mechanisms that regradation responsible for Red pepper shrimp homeostasis in eukaryotes. Ubiquitylation is utilized as a degradation Energy boosters for better mood by proteaomal systems, yet, different mechanisms are in play. The UPS is responsible for Autophagy and proteasomal degradation degradation degtadation short-lived proteins and soluble misfolded proteins whereas autophagy eliminates long-lived proteins, insoluble protein aggregates and even whole organelles e. Both the UPS and selective autophagy recognize their targets through their ubiquitin tags. In addition to an indirect connection between the two systems through ubiquitylated proteins, recent data indicate the presence of connections and reciprocal regulation mechanisms between these degradation pathways. In this review, we summarize these direct and indirect interactions and crosstalks between autophagy and the UPS, and their implications for cellular stress responses and homeostasis. The ubiquitin—proteasome system UPS and macroautophagy hereafter referred as autophagy are two major intracellular protein degradation pathways.