Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy

Abstract

The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

“…USP30 is one of only two DUBs that possess a transmembrane domain. Its localisation is restricted to the outer mitochondrial membrane and to peroxisomes (18)(19)(20)(21). USP30 can limit the Parkin-dependent ubiquitylation of selected substrates and depolarisation-induced mitophagy in cell systems that have been engineered to over-express Parkin (22)(23)(24)(25).…”

Pexophagy: A Model for Selective Autophagy

“…Opposing the action of PEX2 on peroxisomes is the deubiquitinating enzyme USP30 ( Figure 3B). First described as a mitophagy regulator [152], USP30 has been shown independently by two groups to regulate pexophagy by targeting to peroxisomes [103,104]. Marcassa, E., et al found that an endogenous portion of USP30 localizes to peroxisomes via an N-terminal transmembrane domain where it acts to reduce basal pexophagy [103].…”

“…Marcassa, E., et al found that an endogenous portion of USP30 localizes to peroxisomes via an N-terminal transmembrane domain where it acts to reduce basal pexophagy [103]. Riccio, V., et al subsequently reported that over-expression of USP30 prevents amino-acid starvation-induced pexophagy, by counteracting PEX2-mediated ubiquitination of PEX5 and PMP70 [104]. These studies highlight the importance of ubiquitin designation for pexophagy and demonstrate that dissipation of ubiquitin from peroxisomes serves to counteract pexophagy basally and during amino acid starvation.…”

USP30: protector of peroxisomes and mitochondria

“…4 Regulation of pexophagy is therefore essential to prevent disease, and thus formed the basis of our study. 5 Peroxisomes, like mitochondria, are degraded through selective autophagy, termed pexophagy and mitophagy respectively. Pexophagy can be induced by various stimuli, but the focus of our study was amino acid starvation induced pexophagy.…”

“…Our published study aimed to characterize the role of USP30 in peroxisome maintenance. 5 We began by showing the targeting of USP30 to peroxisomes, demonstrating that over-expressed wild type USP30 is colocalized with peroxisomes significantly more than the mitochondrial targeted TOM20-USP30. Using a stop-anchor PEX16 (saPEX16) which is ER retained, we showed that USP30 can be recruited to the ER by the peroxisome membrane importer PEX16, while mitochondrial targeting remained intact, suggesting that USP30 is targeted to the peroxisomes with the assistance of PEX16.…”