bims-mitpro 2025-05-11 papers

Issue of 2025–05–11
three papers selected by
Andreas Kohler, Umeå University

Autophagy. 2025 May 06. 1-3

SNX10 at the crossroad of endocytosis and piecemeal mitophagy.

Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen.

Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.

Keywords: SNX10; endosomal sorting; mitophagy; oxidative stress; zebrafish

DOI: https://doi.org/10.1080/15548627.2025.2499641

Nat Struct Mol Biol. 2025 May 05.

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.

Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch.

The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.

DOI: https://doi.org/10.1038/s41594-025-01534-4

Nat Commun. 2025 May 07. 16(1): 4243

p97/VCP is required for piecemeal autophagy of aggresomes.

Maria Körner, Paul Müller, Hirak Das, Felix Kraus, Timo Pfeuffer, Sven Spielhaupter, Silke Oeljeklaus, Christina Schülein-Völk, J Wade Harper, Bettina Warscheid, Alexander Buchberger.

Metazoan cells adapt to the exhaustion of protein quality control (PQC) systems by sequestering aggregation-prone proteins in large, pericentriolar structures termed aggresomes. Defects in both aggresome formation and clearance affect proteostasis and have been linked to neurodegenerative diseases, but aggresome clearance pathways are still underexplored. Here we show that aggresomes comprising endogenous proteins are cleared via selective autophagy requiring the cargo receptor TAX1BP1. TAX1BP1 proximitomes reveal the presence of various PQC systems at aggresomes, including Hsp70 chaperones, the 26S proteasome, and the ubiquitin-selective unfoldase p97/VCP. While Hsp70 and p97/VCP with its cofactors UFD1-NPL4 and FAF1 play key roles in aggresome disassembly, the 26S proteasome is dispensable. We identify aggresomal client proteins that are degraded via different routes, in part in a p97/VCP-dependent manner via aggrephagy. Upon acute inhibition of p97/VCP, aggresomes fail to disintegrate and cannot be incorporated into autophagosomes despite the presence of factors critical for aggrephagosome formation, including p62/SQSTM1, TAX1BP1, and WIPI2. We conclude that the p97/VCP-mediated removal of ubiquitylated aggresomal clients is essential for the disintegration and subsequent piecemeal autophagy of aggresomes.

DOI: https://doi.org/10.1038/s41467-025-59556-x