The Role of Deubiquitinating Enzymes in the Various Forms of Autophagy

Abstract

Deubiquitinating enzymes (DUBs) have an essential role in several cell biological processes via removing the various ubiquitin patterns as posttranslational modification forms from the target proteins. These enzymes also contribute to the normal cytoplasmic ubiquitin pool during the recycling of this molecule. Autophagy, a summary name of the lysosome dependent self-degradative processes, is necessary for maintaining normal cellular homeostatic equilibrium. Numerous forms of autophagy are known depending on how the cellular self-material is delivered into the lysosomal lumen. In this review we focus on the colorful role of DUBs in autophagic processes and discuss the mechanistic contribution of these molecules to normal cellular homeostasis via the possible regulation forms of autophagic mechanisms.

The role of K63-linked polyubiquitin in several types of autophagy

“…The linkage types are thus discriminated by the proximal moiety's residue: K6-, K11-, K27-, K29-, K33-, K48-, K63-linked polyubiquitin chains can be assembled by isopeptide bonds (Csizmadia and Lőw 2020;Swatek and Komander 2016). A classical peptide bond between the Nand C-termini of two ubiquitin moieties can also be formed, that is either called Methionine1 (Met1)-linked polyubiquitin because of the determining proximal residue, or linear ubiquitin which refers to the continuity of the polypeptide chain between moieties (Rieser et al 2013).…”

“…There are hydrophobic patches and protein interaction sites on the surface of ubiquitin, which either take part in shaping the polyubiquitin chain, or facilitate interaction with other proteins (Komander and Rape 2012). Polyubiquitin chains linked by the same Lysine residues are called homotypic chains, and chains that contain different linkage types are called heterotypic chains (Csizmadia and Lőw 2020;Komander and Rape 2012;Swatek and Komander 2016). More than one polyubiquitin chain could be attached to the substrate proteins, that also applies Fig.…”

Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells

“…Further to this, we suggest that IMP-2373 could be applied to understand the activity of DUBs in other, diverse contexts. For example, future studies could explore the impact of other pathological and physiological processes causing rapid changes in protein turnover, such as the switch to cellular quiescence 52 or senescence in cancer, 53,54 UPS-independent but Ub-dependent degradation pathways such as autophagy or mitophagy, 55 or host-pathogen interactions, for example during infection by viruses which hijack endogenous DUB activity. 56 DUB and Ub substrate selectivity is typically driven by extensive macromolecular interactions, presenting a significant challenge for small molecule DUB probe design which must retain small size to avoid cell impermeability, as is the case for 8 kDa Ub ABPs.…”

Ubiquitin-Specific Protease 29 Regulates Cdc25A-Mediated Tumorigenesis

“…These regulatory proteins are expressed in a cyclic manner when their functions are needed for cellular processes, including cancer progression. This recurring protein expression is governed largely by the ubiquitin proteasome system; however, in recent years, several studies have revealed additional roles for DUBs in various cellular processes [ 23 , 24 , 25 ]. A few reports have revealed the involvement of DUBs in all phases of the cell cycle [ 26 ].…”