Abstract
The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways.
Highlights
Protein Quality Control MechanismsAt the cellular level, cells need to recycle old, abnormal, or dysfunctional proteins and maintain a “healthy” balance between newly-synthesized proteins and existing ones in order to maintain the efficient functioning of cellular pathways and systems
These include toll-interacting protein (TOLLIP), the mammalian homologue of Cue5 [106], SQSTM1, and NBR1, which are the best characterized autophagic receptors that recognize a broad range of substrates and are involved in almost every type of selective autophagy [27,29,30,31,107,108,109,110,111,112,113], OPTN, which is involved in the autophagic clearance of ubiquitinated aggregates, pathogens, and mitochondria [33,114,115,116], and, nuclear dot protein 52 kDa (NDP52), which is required for the autophagic clearance of ubiquitinated mitochondria and pathogens [117,118,119]
The best example of the role of chaperones in modulating and regulating the protein quality control (PQC) pathway choice comes from the studies on the Bcl2-associated athanogene (BAG) family of proteins in mammals, which are implicated in the coordination of proteasomal and autophagic activation
Summary
Cells need to recycle old, abnormal, or dysfunctional proteins and maintain a “healthy” balance between newly-synthesized proteins and existing ones in order to maintain the efficient functioning of cellular pathways and systems. The ATG8/LC3/GABARAP proteins are Ub-like proteins that share structural features with Ub, such as two amino-terminal α helices and a Ub-like core [14,15,16,17,18,19,20] During autophagosome formation, these proteins undergo a unique Ub-like conjugation to phosphatidylethanolamine on the isolation membrane (phagophore, pre-autophagosomal structure), which expands around the substrate(s) and encloses it in a vesicle (autophagosome) for further delivery to, and clearance within, the vacuole (in yeast and plants) or lysosome (in mammals). Aggregates of misfolded proteins are among the various substrates that can be selectively targeted for autophagic clearance [25,26,27,28,29,30,31,32,33] In this process, called aggrephagy, particular autophagic cargo receptors recognize ubiquitinated aggregates and link them to the expanding isolation membrane through their interaction with ATG8/LC3/GABARAP protein family members for subsequent degradation [25]. Based on the structure and properties of the Ub-binding protein shuttles that are the Ub-binding protein shuttles that are used for substrate degradation
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