biostudies-literatureMiao YNational Natural Science Foundation of ChinaNational Key Research and Development Program of ChinaRP96353https://www.ebi.ac.uk/biostudies/studies/S-EPMC11584181biostudies-literatureUnknown13The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulateLifeSpatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation.PMC115841813192100232321004320708102021YFA08058022022YFA13045002021YFA080480292354305Liu JWang BLi DLiang YLiang JMiao YDu YDang SHe KDing MfalseSpatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation.The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulat2024-01-01T00:00:00Z2024 Nov2025-04-04T01:21:24.462Z2025-04-04T01:21:24.462ZS-EPMC115841813957668910.7554/eLife.96353