ATG16 mediates the autophagic degradation of the 19S proteasomal subunits PSMD1 and PSMD2

Xiong, Qiuhong; Fischer, Sarah; Karow, Malte; Müller, Rolf; Meßling, Susanne; Eichinger, Ludwig M.

doi:10.1016/j.ejcb.2018.09.002

Cited by 24 publications

(29 citation statements)

References 68 publications

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“…Interestingly, PSMD1 and PSMD2, the components of the 19S regulatory particle in the proteasome complex, directly interact with ATG16. When ATG16 is bound to PSMD1 or 2, it is degraded by the lysosomes, and ATG16 was an essential component of autophagy progression (38).…”

Section: The Ups and Autophagy Are Tightly Associatedmentioning

confidence: 99%

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

2020

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The ubiquitin-proteasome system (UPS) and autophagy are two major degradative pathways of proteins in eukaryotic cells. As about 30% of newly synthesized proteins are known to be misfolded under normal cell conditions, the precise and timely operation of the UPS and autophagy to remove them as well as their tightly controlled regulation, is so important for proper cell function and survival. In the UPS, target proteins are labeled by small proteins called ubiquitin, which are then transported to the proteasome complex for degradation. Alternatively, many greatly damaged proteins are believed to be delivered to the lysosome for autophagic degradation. Although these autophagy and UPS pathways have not been considered to be directly related, many recent studies proposed their close link and dynamic interconversion. In this review, we'll focus on the several regulatory molecules that function in both UPS and autophagy and their crosstalk. Among the proposed multiple modulators, we will take a closer look at the so-called main connector of UPS-autophagy regulation, p62. Last, the functional role of p62 in the mitophagy and its implication for the pathogenesis of Parkinson's disease, one of the major neurodegenerative diseases, will be briefly reviewed. [

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Section: The Ups and Autophagy Are Tightly Associatedmentioning

confidence: 99%

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

2020

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“…Interestingly, in the model organism Dictyostelium discoideum it could recently be shown that the 19S subunits PSMD1 and PSMD2 directly interact with ATG16, a component of the core autophagy machinery, and are degraded by autophagy dependent on ATG16 45 . This interaction and the following autophagic degradation is dependent on the N-terminal portion of Atg16 containing an Atg5-interacting motif.…”

Section: Discussionmentioning

confidence: 99%

Proteaphagy in Mammalian Cells Can Function Independent of ATG5/ATG7

Goebel¹,

Mausbach²,

Tuermer³

et al. 2020

Molecular & Cellular Proteomics

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The degradation of intra- and extracellular proteins is essential in all cell types and mediated by two systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. This study investigates the changes in autophagosomal and lysosomal proteomes upon inhibition of proteasomes by bortezomib (BTZ) or MG132. We find an increased abundance of more than 50 proteins in lysosomes of cells in which the proteasome is inhibited. Among those are dihydrofolate reductase (DHFR), β-Catenin and 3-hydroxy-3-methylglutaryl-coenzym-A (HMGCoA)-reductase. Because these proteins are known to be degraded by the proteasome they seem to be compensatorily delivered to the autophagosomal pathway when the proteasome is inactivated. Surprisingly, most of the proteins which show increased amounts in the lysosomes of BTZ or MG132 treated cells are proteasomal subunits. Thus an inactivated, non-functional proteasome is delivered to the autophagic pathway. Native gel electrophoresis shows that the proteasome reaches the lysosome intact and not disassembled. Adaptor proteins, which target proteasomes to autophagy, have been described in Arabidopsis, Saccharomyces and upon starvation in mammalians. However, in cell lines deficient of these proteins or their mammalian orthologues, respectively, the transfer of proteasomes to the lysosome is not impaired. Obviously, these proteins do not play a role as autophagy adaptor proteins in mammalian cells. We can also show that chaperone-mediated autophagy (CMA) does not participate in the proteasome delivery to the lysosomes. In autophagy-related (ATG)-5 and ATG7 deficient cells the delivery of inactivated proteasomes to the autophagic pathway was only partially blocked, indicating the existence of at least two different pathways by which inactivated proteasomes can be delivered to the lysosome in mammalian cells.

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“…ATG16 is also involved in Cullin-3-mediated ubiquitination and proteasomal degradation of the selective autophagy adaptor p62/SQSTM1 (Xiong et al, 2019). In Dictyostelium, ATG16 carries out additional functions in proteasomal activity, axenic growth and macropinocytosis (Xiong et al, 2018, Xiong et al, 2019, Xiong et al, 2015. Since the Dictyostelium atg16 knockout mutant displayed strongly reduced proteasomal activity, ATG16 is crucial for optimal UPS function (Xiong et al, 2015).…”

Section: Further Autophagy-independent Functions Of Atg5 Atg12 and Amentioning

confidence: 99%

“…In contrast larger longlived proteins, protein aggregates or even whole organelles are delivered to and degraded in lysosomes via the autophagosomal route (Ciechanover and Kwon, 2015). However, the observation that more than 40 proteins are shared as either substrates or regulators of both autophagy and the UPS, among them core autophagy proteins like ATG5, ATG7, ATG8, and ATG16, has generated interest in analysing the crosstalk between these two pathways (Gao et al, 2010, Komatsu et al, 2005, Mizushima and Levine, 2010, Nam et al, 2017, Xiong et al, 2018. The most crucial common denominator of both degradative pathways is ubiquitination as degradation signal on substrates (Kraft et al, 2010).…”

Section: Crosstalk Between Autophagy and The Ubiquitin-proteasome Sysmentioning

confidence: 99%

“…It was also shown that PSMD1/2 get degraded in lysosomes. However, it is currently not clear how the interaction between ATG16 and PSMD1/2 is regulated and whether this interaction is responsible for proteaphagy in D. discoideum (Xiong et al, 2018). Taken together, the data suggest that in autophagy-compromised D. discoideum strains less active or inactive proteasomes accumulate, which would cause the observed dramatic decrease in proteasomal activity (Arhzaouy et al, 2012, Fischer et al, 2019, Messling et al, 2017, Xiong et al, 2015.…”

Section: Crosstalk Between Autophagy and The Ubiquitin-proteasome Sysmentioning

confidence: 99%

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Dictyostelium discoideum and autophagy – a perfect pair

Fischer¹,

Eichinger²

2019

Int. J. Dev. Biol.

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Autophagy is subdivided into chaperone-mediated autophagy, microautophagy and macroautophagy and is a highly conserved intracellular degradative pathway. It is crucial for cellular homeostasis and also serves as a response to different stresses. Here we focus on macroautophagy, which targets damaged organelles and large protein assemblies, as well as pathogenic intracellular microbes for destruction. During this process, cytosolic material becomes enclosed in newly generated double-membrane vesicles, the so-called autophagosomes. Upon maturation, the autophagosome fuses with the lysosome for degradation of the cargo. The basic molecular machinery that controls macroautophagy works in a sequential order and consists of the ATG1 complex, the PtdIns3K complex, the membrane delivery system, two ubiquitin-like conjugation systems, and autophagy adaptors and receptors. Since the different stages of macroautophagy from initiation to final degradation of cargo are tightly regulated and highly conserved across eukaryotes, simple model organisms in combination with a wide range of techniques contributed significantly to advance our understanding of this complex dynamic process. Here, we present the social amoeba Dictyostelium discoideum as an advantageous and relevant experimental model system for the analysis of macroautophagy.KEY WORDS: autophagy, ubiquitin-proteasome system (UPS), LC3-associated phagocytosis, proteaphagy Int. J. Dev. Biol. 63: 485-495 (2019)

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ATG16 mediates the autophagic degradation of the 19S proteasomal subunits PSMD1 and PSMD2

Cited by 24 publications

References 68 publications

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

Proteaphagy in Mammalian Cells Can Function Independent of ATG5/ATG7

Dictyostelium discoideum and autophagy – a perfect pair

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