Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation

Miao, Y.; Du, Y.; Wang, B.; Liang, J.; Liang, Y.; Dang, S.; Liu, J.; Li, D.; He, K.; Ding, M.

doi:10.1101/2024.01.10.575034

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bioRxiv · 10.1101/2024.01.10.575034

Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation

Miao, Y.·Du, Y.·Wang, B.·Liang, J.·Liang, Y.·Dang, S.·Liu, J.·Li, D.·He, K.·Ding, M.

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Abstract

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 accumulate and digestive lysosomes are rudimentary. Together, our results reveal an important and unexpected role of a deubiquitinating enzyme in endosome maturation.

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Miao, Y., Du, Y., Wang, B., Liang, J., Liang, Y., Dang, S., Liu, J., Li, D., He, K., Ding, M.. 2024-01-11. Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation. https://doi.org/10.1101/2024.01.10.575034

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