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

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.