Dual function of the Leon/USP5 deubiquitinase in the ubiquitin-proteasome and autophagic pathways

Abstract

The ubiquitin-proteasome system (UPS) and autophagy are highly conserved processes that maintain cellular health through the clearance of misfolded/aberrant proteins and damaged organelles. Ubiquitination is a crucial protein modification to regulate entry in these two pathways. However, the function of deubiquitinases (DUBs) in the UPS and autophagy remains largely unclear. The Leon/USP5 deubiquitinase is essential for maintaining ubiquitin homeostasis and proteasome function. In our recent study, we found that Leon/USP5 depletion resulted in the induction of autophagosome formation and an enhancement of the autophagic flux. Additionally, a genetic analysis in Drosophila revealed that Leon overexpression suppressed Atg1-induced cell death. We further showed that Leon/USP5 interacts with the autophagy initiator Atg1/ULK1, regulating its levels and thus modulating autophagosome formation. These findings suggest that Leon/USP5 plays a dual role in regulation of UPS and autophagy. Abbreviations: Atg1: autophagy-related 1; Atg7: autophagy-related 7; DUB: deubiquitinase; ED: enzyme dead; PTM: post-translational modification; SQSTM1: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; USP5: ubiquitin-specific proteinase 5; WT: wild-type.

Keywords: Atg1/ULK1; Leon/USP5; Ref(2)P/SQSTM1; autophagy; deubiquitinase.

Figure 1.

Schematic diagram of Leon/USP5 function in the ubiquitin-proteasome system (UPS) and autophagy. Leon/USP5 controls the protein quality through proteasomal degradation. Simultaneously, Leon/USP5 maintains ubiquitin homeostasis by cleaving unanchored polyubiquitin chains. Additionally, Leon/USP5 negatively regulates autophagy processby targeting Atg1/ULK1.