Ubiquitin-mediated regulation of autophagy

Abstract

Autophagy is a major degradation pathway that utilizes lysosome hydrolases to degrade cellular constituents and is often induced under cellular stress conditions to restore cell homeostasis. Another prime degradation pathway in the cells is ubiquitin-proteasome system (UPS), in which proteins tagged by certain types of polyubiquitin chains are selectively recognized and removed by proteasome. Although the two degradation pathways are operated independently with different sets of players, recent studies have revealed reciprocal cross talks between UPS and autophagy at multiple layers. In this review, we summarize the roles of protein ubiquitination and deubiquitination in controlling the initiation, execution, and termination of bulk autophagy as well as the role of ubiquitination in signaling certain types of selective autophagy. We also highlight how dysregulation of ubiquitin-mediated autophagy pathways is associated with a number of human diseases and the potential of targeting these pathways for disease intervention.

Keywords: Autophagy; Deubiquitinating enzyme; Protein ubiquitination; Selective autophagy; Ubiquitin E3 ligase.

Fig. 1

Functional roles of ubiquitin ligases in regulating autophagy. Summary of the proteins acting in the initiation (a), autophagosome biogenesis (b), and autophagosome maturation (c) steps of the autophagic process that are subjected to ubiquitination by various E3 ligases. The ubiquitin chain types and the effect of ubiquitination on autophagy (promotion or inhibition) are indicated

Fig. 2

Functional roles of DUBs in regulating autophagy initiation. Summary of DUBs that regulate autophagy initiation by targeting ULK1 or Beclin-1. The ubiquitin chain types and the effect of ubiquitination on autophagy (promotion or inhibition) are indicated

Fig. 3

Mechanisms for ubiquitin-mediated autophagy termination. The ULK1 and VPS34 complexes are stable in the induction phase of autophagy. After the execution phase of autophagy, several components of the two complexes are degraded via direct or indirect action of indicated E3 ligases, thereby contributing to autophagy termination

Fig. 4

Ubiquitin-dependent selective autophagy. Summary of the molecular mechanisms of major types of selective autophagy using protein ubiquitination as a mark of the cargo. The E3 ligases and DUB involved in generating or removing the ubiquitin chain and the autophagy adaptors used to link ubiquitinated cargos to LC3 are indicated