A guide to the regulation of selective autophagy receptors

Abstract

Autophagy is a highly conserved catabolic process cells use to maintain their homeostasis by degrading misfolded, damaged and excessive proteins, nonfunctional organelles, foreign pathogens and other cellular components. Hence, autophagy can be nonselective, where bulky portions of the cytoplasm are degraded upon stress, or a highly selective process, where preselected cellular components are degraded. To distinguish between different cellular components, autophagy employs selective autophagy receptors, which will link the cargo to the autophagy machinery, thereby sequestering it in the autophagosome for its subsequent degradation in the lysosome. Autophagy receptors undergo post-translational and structural modifications to fulfil their role in autophagy, or upon executing their role, for their own degradation. We highlight the four most prominent protein modificationsphosphorylation, ubiquitination, acetylation and oligomerisationthat are essential for autophagy receptor recruitment, function and turnover. Understanding the regulation of selective autophagy receptors will provide deeper insights into the pathway and open up potential therapeutic avenues.

Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy

“…The observation that TAX1BP1 is major receptor for lysophagy extends recent work identifying roles for protein in various selective autophagic pathways (Gubas and Dikic, 2021) TAX1BP1 likely plays a dual role, as it interacts with both TBK1 and the RB1CC1-ULK1-ATG13 complex through its SKICH domain (Figure 8I). This may allow TAX1BP1 to orchestrate signaling via both of these kinase complexes, and could possibly promote autophagosome formation directly via recruitment of ULK1 to cargo (Ravenhill et al, 2019;Shi et al, 2020;Turco et al, 2020;Vargas et al, 2019) In addition, TAX1BP1 appears to have diverse cargo, ranging from membranous organelles as shown here to ubiquitylated protein aggregates as recently described (Sarraf et al, 2020).…”

“…ERphagy), receptor proteins typically embedded in the cognate membrane are directly recognized by the autophagic machinery to facilitate engulfment in response to regulatory signals. These cargo receptors employ LC3-interacting region (LIR) motifs to associate with the LIR-docking site (LDS) in one or more of 6 ATG8 adaptor proteins that are located in the growing autophagosomal membrane by virtue of attachment to phosphatidylethanolamine via their C-terminal glycine residue (Gubas and Dikic, 2021;Johansen and Lamark, 2020). In contrast, Ub-dependent forms of organellophagy frequently employ a multistep process involving: 1) sensing of organelle damage, 2) ubiquitylation of one or more proteins associated with the membrane of the damaged organelle, 3) recruitment of one or more Ub-binding autophagy receptors containing LIR or other motifs that recruit autophagic machinery, and 4) expansion of the autophagic membrane around the organelle, thereby facilitating delivery to the lysosome (Gubas and Dikic, 2021;Johansen and Lamark, 2020;Khaminets et al, 2016;Lamark and Johansen, 2021).…”

“…These cargo receptors employ LC3-interacting region (LIR) motifs to associate with the LIR-docking site (LDS) in one or more of 6 ATG8 adaptor proteins that are located in the growing autophagosomal membrane by virtue of attachment to phosphatidylethanolamine via their C-terminal glycine residue (Gubas and Dikic, 2021;Johansen and Lamark, 2020). In contrast, Ub-dependent forms of organellophagy frequently employ a multistep process involving: 1) sensing of organelle damage, 2) ubiquitylation of one or more proteins associated with the membrane of the damaged organelle, 3) recruitment of one or more Ub-binding autophagy receptors containing LIR or other motifs that recruit autophagic machinery, and 4) expansion of the autophagic membrane around the organelle, thereby facilitating delivery to the lysosome (Gubas and Dikic, 2021;Johansen and Lamark, 2020;Khaminets et al, 2016;Lamark and Johansen, 2021). This pathway is perhaps best understood in the context of damaged mitochondria, where the Parkin Ub ligase catalyzes ubiquitylation of mitochondrial outer membrane proteins, followed by recruitment of multiple Ub-binding autophagy receptors including Optineurin (OPTN), CALCOCO2 (also called NDP52), SQSTM1 (also called p62), TAX1BP1, and NBR1 to the outer membrane (Harper et al, 2018;Heo et al, 2015;Lazarou et al, 2015;Moore and Holzbaur, 2016;Ordureau et al, 2014Ordureau et al, , 2018Ordureau et al, , 2020Pickrell and Youle, 2015;Richter et al, 2016;Wong and Holzbaur, 2014).…”

The WIPI Gene Family and Neurodegenerative Diseases: Insights From Yeast and Dictyostelium Models

“…Macroautophagy (referred to as autophagy hereafter) is characterized by the formation of double-membrane vesicles, known as autophagosomes, which can engulf non-specific cellular material (bulk autophagy) or specific cargoes, such as protein aggregates or defective organelles (selective autophagy). After the fusion of autophagosomes with the lysosomes, the simple biochemical compounds generated during the degradation process are transported to the cytosol and reused for energy production or recycling (see recent reviews Lahiri et al, 2019 ; Melia et al, 2020 ; Gubas and Dikic, 2021 ). Autophagosome biogenesis is a highly regulated process involving different stages: induction, lipidation, and elongation of the autophagosome membrane (also known as the isolation membrane or phagophore), vesicle closure, and fusion with lysosomes.…”

Go for the Golgi: Eating selectively with Calcoco1

“…As a result, observations across multiple studies have revealed that many of the cargo receptors are not exclusive to one type of cargo but shared by many. For example, the most commonly studied adaptor protein, p62/SQSTM1, has been implicated in the turnover of a broad range of cargoes from peroxisomes, ER, and mitochondria to protein aggregates and bacteria ( 1 , 2 , 3 ). This is not unique to p62/SQSTM1, as Optineurin and Calcoco2/NDP52 have been shown to coordinate the turnover of not only multiple cargoes, but in some instances, the same type of cargo.…”