Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-019-09437-x
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Funding
- UPStream network - Marie Curie Initial Training Network (ITN) grant from the European Union (FP7A-PEOPLE-2011-ITN)
- Innovational Research Incentives Scheme Vici grant from the Netherlands Foundation for Scientific Research (N.W.O.) [724.013.002]
- ERC Advanced grants
- European Cooperation in Science and Technology (COST)
- short-term scientific mission grant (STSM)
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The endosomal system is a highly dynamic multifunctional organelle, whose complexity is regulated in part by reversible ubiquitylation. Despite the wide-ranging influence of ubiquitin in endosomal processes, relatively few enzymes utilizing ubiquitin have been described to control endosome integrity and function. Here we reveal the deubiquitylating enzyme (DUB) ubiquitin-specific protease 32 (USP32) as a powerful player in this context. Loss of USP32 inhibits late endosome (LE) transport and recycling of LE cargos, resulting in dispersion and swelling of the late compartment. Using SILAC-based ubiquitome profiling we identify the small GTPase Rab7-the logistical centerpiece of LE biology-as a substrate of USP32. Mechanistic studies reveal that LE transport effector RILP prefers ubiquitylation-deficient Rab7, while retromer-mediated LE recycling benefits from an intact cycle of Rab7 ubiquity-lation. Collectively, our observations suggest that reversible ubiquitylation helps switch Rab7 between its various functions, thereby maintaining global spatiotemporal order in the endosomal system.
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