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Open AccessEditorial

Special Issue on “Ubiquitin and Autophagy”

by Taras Y. Nazarko

Cells 2021, 10(1), 116; https://doi.org/10.3390/cells10010116 - 10 Jan 2021

Viewed by 2218

Abstract

The Special Issue of Cells on “Ubiquitin and Autophagy” is a tribute to the multifaceted role of ubiquitin and autophagic ubiquitin-like (UBL) proteins in the autophagy-related (ATG) pathways [...] Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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18 pages, 3063 KiB

Open AccessArticle

TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy

by Hyun Je Kang, Eun Jin Yoo, Hwan Hee Lee, Seung Min An, Hyun Park, Whaseon Lee-Kwon, Soo Youn Choi and Hyug Moo Kwon

Cells 2020, 9(9), 1928; https://doi.org/10.3390/cells9091928 - 20 Aug 2020

Cited by 4 | Viewed by 3352

Abstract

The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both [...] Read more.

The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which TonEBP was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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16 pages, 2467 KiB

Open AccessArticle

Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in C. elegans

by Sweta Jha and Carina I. Holmberg

Cells 2020, 9(8), 1858; https://doi.org/10.3390/cells9081858 - 8 Aug 2020

Cited by 6 | Viewed by 3514

Abstract

The ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are the two main eukaryotic intracellular proteolytic systems involved in maintaining proteostasis. Several studies have reported on the interplay between the UPS and ALP, however it remains largely unknown how compromised autophagy affects UPS [...] Read more.

The ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are the two main eukaryotic intracellular proteolytic systems involved in maintaining proteostasis. Several studies have reported on the interplay between the UPS and ALP, however it remains largely unknown how compromised autophagy affects UPS function in vivo. Here, we have studied the crosstalk between the UPS and ALP by investigating the tissue-specific effect of autophagy genes on the UPS at an organismal level. Using transgenic Caenorhabditis elegans expressing fluorescent UPS reporters, we show that the downregulation of the autophagy genes lgg-1 and lgg-2 (ATG8/LC3/GABARAP), bec-1 (BECLIN1), atg-7 (ATG7) and epg-5 (mEPG5) by RNAi decreases proteasomal degradation, concomitant with the accumulation of polyubiquitinated proteasomal substrates in a tissue-specific manner. For some of these genes, the changes in proteasomal degradation occur without a detectable alteration in proteasome tissue expression levels. In addition, the lgg-1 RNAi-induced reduction in proteasome activity in intestinal cells is not dependent on sqst-1/p62 accumulation. Our results illustrate that compromised autophagy can affect UPS in a tissue-specific manner, and demonstrate that UPS does not function as a direct compensatory mechanism in an animal. Further, a more profound understanding of the multilayered crosstalk between UPS and ALP can facilitate the development of therapeutic options for various disorders linked to dysfunction in proteostasis. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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23 pages, 4399 KiB

Open AccessArticle

Functional Characterisation of the Autophagy ATG12~5/16 Complex in Dictyostelium discoideum

by Malte Karow, Sarah Fischer, Susanne Meßling, Roman Konertz, Jana Riehl, Qiuhong Xiong, Ramesh Rijal, Prerana Wagle, Christoph S. Clemen and Ludwig Eichinger

Cells 2020, 9(5), 1179; https://doi.org/10.3390/cells9051179 - 9 May 2020

Cited by 16 | Viewed by 4567

Abstract

Macroautophagy, a highly conserved and complex intracellular degradative pathway, involves more than 20 core autophagy (ATG) proteins, among them the hexameric ATG12~5/16 complex, which is part of the essential ubiquitin-like conjugation systems in autophagy. Dictyostelium discoideum atg5 single, atg5/12 double, and atg5/12/16 triple [...] Read more.

Macroautophagy, a highly conserved and complex intracellular degradative pathway, involves more than 20 core autophagy (ATG) proteins, among them the hexameric ATG12~5/16 complex, which is part of the essential ubiquitin-like conjugation systems in autophagy. Dictyostelium discoideum atg5 single, atg5/12 double, and atg5/12/16 triple gene knock-out mutant strains displayed similar defects in the conjugation of ATG8 to phosphatidylethanolamine, development, and cell viability upon nitrogen starvation. This implies that ATG5, 12 and 16 act as a functional unit in canonical autophagy. Macropinocytosis of TRITC dextran and phagocytosis of yeast were significantly decreased in ATG5¯ and ATG5¯/12¯ and even further in ATG5¯/12¯/16¯ cells. In contrast, plaque growth on Klebsiella aerogenes was about twice as fast for ATG5¯ and ATG5¯/12¯/16¯ cells in comparison to AX2, but strongly decreased for ATG5¯/12¯ cells. Along this line, phagocytic uptake of Escherichia coli was significantly reduced in ATG5¯/12¯ cells, while no difference in uptake, but a strong increase in membrane association of E. coli, was seen for ATG5¯ and ATG5¯/12¯/16¯ cells. Proteasomal activity was also disturbed in a complex fashion, consistent with an inhibitory activity of ATG16 in the absence of ATG5 and/or ATG12. Our results confirm the essential function of the ATG12~5/16 complex in canonical autophagy, and furthermore are consistent with autophagy-independent functions of the complex and its individual components. They also strongly support the placement of autophagy upstream of the ubiquitin-proteasome system (UPS), as a fully functional UPS depends on autophagy. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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14 pages, 3480 KiB

Open AccessEditor’s ChoiceArticle

p62 is Negatively Implicated in the TRAF6-BECN1 Signaling Axis for Autophagy Activation and Cancer Progression by Toll-Like Receptor 4 (TLR4)

by Mi-Jeong Kim, Yoon Min, Ji Seon Im, Juhee Son, Joo Sang Lee and Ki-Young Lee

Cells 2020, 9(5), 1142; https://doi.org/10.3390/cells9051142 - 6 May 2020

Cited by 28 | Viewed by 4527

Abstract

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 [...] Read more.

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 negatively regulates Toll-like receptor 4 (TLR4)-mediated signaling via TRAF6-ECSIT signaling axis, we herein investigated whether p62 is functionally implicated in the TRAF6-BECN1 signaling axis, thereby regulating cancer cell migration and invasion. p62 interacted with TRAF6 and BECN1, to interrupt the functional associations required for TRAF6-BECN1 complex formation, leading to inhibitions of BECN1 ubiquitination and autophagy activation. Importantly, p62-deficient cancer cells, such as p62-knockdown (p62^KD) SK-HEP-1, p62^KD MDA-MB-231, and p62-knockout (p62^KO) A549 cells, showed increased activation of autophagy induced by TLR4 stimulation, suggesting that p62 negatively regulates autophagy activation. Moreover, these p62-deficient cancer cells exhibited marked increases in cell migration and invasion in response to TLR4 stimulation. Collectively, these results suggest that p62 is negatively implicated in the TRAF6-BECN1 signaling axis, thereby inhibiting cancer cell migration and invasion regulated by autophagy activation in response to TLR4 stimulation. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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27 pages, 10880 KiB

Open AccessArticle

Impairment of Proteasome and Autophagy Underlying the Pathogenesis of Leukodystrophy

by Dar-Shong Lin, Che-Sheng Ho, Yu-Wen Huang, Tsu-Yen Wu, Tsung-Han Lee, Zo-Darr Huang, Tuan-Jen Wang, Shun-Jie Yang and Ming-Fu Chiang

Cells 2020, 9(5), 1124; https://doi.org/10.3390/cells9051124 - 1 May 2020

Cited by 17 | Viewed by 4254

Abstract

Impairment of the ubiquitin-proteasome-system (UPS) and autophagy causing cytoplasmic aggregation of ubiquitin andp62 have been implicated in the pathogenesis of most neurodegenerative disorders, yet, they have not been fully elucidated in leukodystrophies. The relationship among impairment of UPS, autophagy, and globoid cell leukodystrophy [...] Read more.

Impairment of the ubiquitin-proteasome-system (UPS) and autophagy causing cytoplasmic aggregation of ubiquitin andp62 have been implicated in the pathogenesis of most neurodegenerative disorders, yet, they have not been fully elucidated in leukodystrophies. The relationship among impairment of UPS, autophagy, and globoid cell leukodystrophy (GLD), one of the most common demyelinating leukodystrophies, is clarified in this study. We examined the ubiquitin and autophagy markers in the brains of twitcher mice, a murine model of infantile GLD, and in human oligodendrocytes incubated with psychosine. Immunohistochemical examinations showed spatiotemporal accumulation of ubiquitin- and p62-aggregates mainly in the white matter of brain and spinal cord at disease progression. Western blot analysis demonstrated a significant accumulation of ubiquitin, p62, and LC3-II in insoluble fraction in parallel with progressive demyelination and neuroinflammation in twitcher brains. In vitro study validated a dose- and time-dependent cytotoxicity of psychosine upon autophagy and UPS machinery. Inhibition of autophagy and UPS exacerbated the accumulation of insoluble ubiquitin, p62, and LC3-II proteins mediated by psychosine cytotoxicity as well as increased cytoplasmic deposition of ubiquitin- and p62-aggregates, and accumulation of autophagosomes and autolysosomes. Further, the subsequent accumulation of reactive oxygen species and reduction of mitochondrial respiration led to cell death. Our studies validate the impairment of proteasome and autophagy underlying the pathogenesis of GLD. These findings provide a novel insight into pathogenesis of GLD and suggest a specific pathomechanism as an ideal target for therapeutic approaches. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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19 pages, 4107 KiB

Open AccessArticle

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

by Steve Catarino, Teresa M Ribeiro-Rodrigues, Rita Sá Ferreira, José Ramalho, Christine Abert, Sascha Martens and Henrique Girão

Cells 2020, 9(4), 902; https://doi.org/10.3390/cells9040902 - 7 Apr 2020

Cited by 5 | Viewed by 4671

Abstract

Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct communication between adjacent cells. Cx43 ubiquitination has been suggested to induce the internalization of GJs, as well as the recruitment of the autophagy receptor p62 to mediate binding to [...] Read more.

Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct communication between adjacent cells. Cx43 ubiquitination has been suggested to induce the internalization of GJs, as well as the recruitment of the autophagy receptor p62 to mediate binding to LC3B and degradation by macroautophagy. In this report, we describe a functional LC3 interacting region (LIR), present in the amino terminal of most Cx protein family members, which can mediate the autophagy degradation of Cx43 without the need of ubiquitin. Mutation of the LIR motif on Cx37, Cx43, Cx46 and Cx50 impairs interaction with LC3B and GABARAP without compromising protein ubiquitination. Through in vitro protein-protein interaction assays, we demonstrate that this LIR motif is required for the binding of Cx43 to LC3B and GABARAP. Overall, our findings describe an alternative mechanism whereby Cxs interact with LC3/GABARAP proteins, envisioning a new model for the autophagy degradation of connexins. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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24 pages, 8823 KiB

Open AccessArticle

The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

by Hianara A Bustamante, Karina Cereceda, Alexis E González, Guillermo E Valenzuela, Yorka Cheuquemilla, Sergio Hernández, Eloisa Arias-Muñoz, Cristóbal Cerda-Troncoso, Susanne Bandau, Andrea Soza, Gudrun Kausel, Bredford Kerr, Gonzalo A Mardones, Jorge Cancino, Ronald T Hay, Alejandro Rojas-Fernandez and Patricia V Burgos

Cells 2020, 9(3), 777; https://doi.org/10.3390/cells9030777 - 23 Mar 2020

Cited by 13 | Viewed by 5365

Abstract

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of [...] Read more.

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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Review

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26 pages, 10281 KiB

Open AccessReview

Sorting Nexins in Protein Homeostasis

by Sara E. Hanley and Katrina F. Cooper

Cells 2021, 10(1), 17; https://doi.org/10.3390/cells10010017 - 24 Dec 2020

Cited by 37 | Viewed by 6126

Abstract

Protein homeostasis is maintained by removing misfolded, damaged, or excess proteins and damaged organelles from the cell by three major pathways; the ubiquitin-proteasome system, the autophagy-lysosomal pathway, and the endo-lysosomal pathway. The requirement for ubiquitin provides a link between all three pathways. Sorting [...] Read more.

Protein homeostasis is maintained by removing misfolded, damaged, or excess proteins and damaged organelles from the cell by three major pathways; the ubiquitin-proteasome system, the autophagy-lysosomal pathway, and the endo-lysosomal pathway. The requirement for ubiquitin provides a link between all three pathways. Sorting nexins are a highly conserved and diverse family of membrane-associated proteins that not only traffic proteins throughout the cells but also provide a second common thread between protein homeostasis pathways. In this review, we will discuss the connections between sorting nexins, ubiquitin, and the interconnected roles they play in maintaining protein quality control mechanisms. Underlying their importance, genetic defects in sorting nexins are linked with a variety of human diseases including neurodegenerative, cardiovascular diseases, viral infections, and cancer. This serves to emphasize the critical roles sorting nexins play in many aspects of cellular function. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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22 pages, 1020 KiB

Open AccessReview

Selective Autophagy by Close Encounters of the Ubiquitin Kind

by Anna Vainshtein and Paolo Grumati

Cells 2020, 9(11), 2349; https://doi.org/10.3390/cells9112349 - 24 Oct 2020

Cited by 29 | Viewed by 5019

Abstract

Autophagy, a bulk degradation process within eukaryotic cells, is responsible for cellular turnover and nutrient liberation during starvation. Increasing evidence indicate that this process can be extremely discerning. Selective autophagy segregates and eliminates protein aggregates, damaged organelles, and invading organisms. The specificity of [...] Read more.

Autophagy, a bulk degradation process within eukaryotic cells, is responsible for cellular turnover and nutrient liberation during starvation. Increasing evidence indicate that this process can be extremely discerning. Selective autophagy segregates and eliminates protein aggregates, damaged organelles, and invading organisms. The specificity of this process is largely mediated by post-translational modifications (PTMs), which are recognized by autophagy receptors. These receptors grant autophagy surgical precision in cargo selection, where only tagged substrates are engulfed within autophagosomes and delivered to the lysosome for proteolytic breakdown. A growing number of selective autophagy receptors have emerged including p62, NBR1, OPTN, NDP52, TAX1BP1, TOLLIP, and more continue to be uncovered. The most well-documented PTM is ubiquitination and selective autophagy receptors are equipped with a ubiquitin binding domain and an LC3 interacting region which allows them to physically bridge cargo to autophagosomes. Here, we review the role of ubiquitin and ubiquitin-like post-translational modifications in various types of selective autophagy. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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16 pages, 1386 KiB

Open AccessReview

Interplay between the Ubiquitin Proteasome System and Ubiquitin-Mediated Autophagy in Plants

by Tong Su, Mingyue Yang, Pingping Wang, Yanxiu Zhao and Changle Ma

Cells 2020, 9(10), 2219; https://doi.org/10.3390/cells9102219 - 1 Oct 2020

Cited by 32 | Viewed by 4611

Abstract

All eukaryotes rely on the ubiquitin-proteasome system (UPS) and autophagy to control the abundance of key regulatory proteins and maintain a healthy intracellular environment. In the UPS, damaged or superfluous proteins are ubiquitinated and degraded in the proteasome, mediated by three types of [...] Read more.

All eukaryotes rely on the ubiquitin-proteasome system (UPS) and autophagy to control the abundance of key regulatory proteins and maintain a healthy intracellular environment. In the UPS, damaged or superfluous proteins are ubiquitinated and degraded in the proteasome, mediated by three types of ubiquitin enzymes: E1s (ubiquitin activating enzymes), E2s (ubiquitin conjugating enzymes), and E3s (ubiquitin protein ligases). Conversely, in autophagy, a vesicular autophagosome is formed that transfers damaged proteins and organelles to the vacuole, mediated by a series of ATGs (autophagy related genes). Despite the use of two completely different componential systems, the UPS and autophagy are closely interconnected and mutually regulated. During autophagy, ATG8 proteins, which are autophagosome markers, decorate the autophagosome membrane similarly to ubiquitination of damaged proteins. Ubiquitin is also involved in many selective autophagy processes and is thus a common factor of the UPS and autophagy. Additionally, the components of the UPS, such as the 26S proteasome, can be degraded via autophagy, and conversely, ATGs can be degraded by the UPS, indicating cross regulation between the two pathways. The UPS and autophagy cooperate and jointly regulate homeostasis of cellular components during plant development and stress response. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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31 pages, 3218 KiB

Open AccessEditor’s ChoiceReview

The Roles of Ubiquitin in Mediating Autophagy

by Zhangyuan Yin, Hana Popelka, Yuchen Lei, Ying Yang and Daniel J. Klionsky

Cells 2020, 9(9), 2025; https://doi.org/10.3390/cells9092025 - 2 Sep 2020

Cited by 64 | Viewed by 8017

Abstract

Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that [...] Read more.

Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that are attached as labels to protein aggregates or subcellular organelles confer selectivity, allowing autophagy receptors to simultaneously bind ubiquitinated cargos and autophagy-specific ubiquitin-like modifiers (Atg8-family proteins). Moreover, there is tremendous crosstalk between autophagy and the ubiquitin-proteasome system. Ubiquitination of autophagy-related proteins or regulatory components plays significant roles in the precise control of the autophagy pathway. In this review, we summarize and discuss the molecular mechanisms and functions of ubiquitin and ubiquitination, in the process and regulation of autophagy. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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16 pages, 849 KiB

Open AccessReview

Ubiquitin, Autophagy and Neurodegenerative Diseases

by Yoshihisa Watanabe, Katsutoshi Taguchi and Masaki Tanaka

Cells 2020, 9(9), 2022; https://doi.org/10.3390/cells9092022 - 2 Sep 2020

Cited by 49 | Viewed by 7156

Abstract

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin–proteasome system and the autophagy–lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into [...] Read more.

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin–proteasome system and the autophagy–lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into autophagosomes. Autophagy receptors possessing an LC3-binding domain and a ubiquitin binding domain are involved in this process. Autophagy activity can decline as a result of genetic variation, aging, or lifestyle, resulting in the onset of various neurodegenerative diseases. This review summarizes the selective autophagy of neurodegenerative disease-associated protein aggregates via autophagy receptors and discusses its therapeutic application for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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25 pages, 4157 KiB

Open AccessEditor’s ChoiceReview

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

by Nicole Wesch, Vladimir Kirkin and Vladimir V. Rogov

Cells 2020, 9(9), 2008; https://doi.org/10.3390/cells9092008 - 1 Sep 2020

Cited by 46 | Viewed by 6247

Abstract

Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis [...] Read more.

Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis of autophagy is formed along the interactions of autophagy modifiers (Atg8-family proteins) with a variety of their cellular counter partners. Besides autophagy, Atg8-proteins participate in many other pathways, among which membrane trafficking and neuronal signaling are the most known. Despite the fact that autophagy modifiers are well-studied, as the small globular proteins show similarity to ubiquitin on a structural level, the mechanism of their interactions are still not completely understood. A thorough analysis and classification of all known mechanisms of Atg8-protein interactions could shed light on their functioning and connect the pathways involving Atg8-proteins. In this review, we present our views of the key features of the Atg8-proteins and describe the basic principles of their recognition and binding by interaction partners. We discuss affinity and selectivity of their interactions as well as provide perspectives for discovery of new Atg8-interacting proteins and therapeutic approaches to tackle major human diseases. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

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