New aspects of USP30 biology in the regulation of pexophagy

Abstract

Mitochondria and peroxisomes have a number of features in common: they each play interconnected roles in fatty acid and reactive oxygen species (ROS) metabolism and, once damaged, need to be removed by specialized autophagic mechanisms, termed mitophagy and pexophagy, respectively. Both processes can use ubiquitin as an initiating signal but whereas mitophagy has been extensively studied, pexophagy remains rather poorly understood. Our recent work, along with a new study from Kim and colleagues, has shed light on the molecular mechanism of pexophagy and the importance of reversible ubiquitination in its regulation. Collectively, these studies highlight the physiological role of the deubiquitinase USP30 in suppressing the turnover of peroxisomes. Abbreviations: ROS: reactive oxygen species; DUB: deubiquitinase or deubiquitylase; USP: ubiquitin specific protease; PINK1: PTEN induced kinase 1; CAT: catalase; KO: knock-out; SQSTM1/p62: sequestosome 1; LIR: LC3 interacting region; GFP: green fluorescent protein; RFP: red fluorescent protein; CRISPR: Clustered Regularly Interspaced Short Palendromic Repeat.

Keywords: Mitochondria; Peroxisomes; Pexophagy; USP30; Ubiquitin.

Figure 1.

Proposed model for USP30-dependent regulation of pexophagy. A discrete pool of USP30 is localized to peroxisomes where it deubiquitinates the peroxisomal membrane protein ABCD3 and the PTS1-receptor PEX5, opposing the ubiquitin E3 ligase PEX2. Ubiquitinated species of ABCD3 and PEX5 serve as a platform for the recruitment of selective autophagy receptor proteins (SQSTM1 and NBR1), that are then recognized and bound by LC3-positive phagophore membranes. (U, ubiquitin; R, receptor).