SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

ADP-Ribosylation Factors/*metabolism ; Adaptor Proteins, Signal Transducing/*metabolism ; GTPase-Activating Proteins/*metabolism ; rab GTP-Binding Proteins/*metabolism; ADP-Ribosylation Factors/genetics ; Adaptor Proteins, Signal Transducing/genetics ; Cell Compartmentation ; Endosomes/metabolism ; GTPase-Activating Proteins/genetics ; HEK293 Cells ; Humans ; Lysosomes/metabolism ; Protein Binding ; Protein Transport ; rab GTP-Binding Proteins/genetics ; rab7 GTP-Binding Proteins

The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by small membrane-bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to regain functional autonomy is unknown. Here, we report that Arl8b employs its effector SKIP to instigate inactivation and removal of Rab7 from select membranes. We find that SKIP interacts with Rab7 and functions as its negative effector, delivering the cognate GAP, TBC1D15. Recruitment of TBC1D15 to SKIP occurs via the HOPS complex, whose assembly is facilitated by contacts between Rab7 and the KMI motif of SKIP. Consequently, SKIP mediates reinstatement of single identity Arl8b sub-compartment through an ordered Rab7-to-Arl8b handover, and, together with Rab7's positive effector RILP, enforces spatial, temporal and morphological compartmentalization of endolysosomal organelles.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

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21098 International Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO); 50438 International EC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC)

Keywords: HOPS; SKIP; Arl8b; Rab7; TBC1D15

0 (ARL8B protein, human)
0 (Adaptor Proteins, Signal Transducing)
0 (GTPase-Activating Proteins)
0 (RILP protein, human)
0 (SPHKAP protein, human)
0 (TBC1D15 protein, human)
0 (rab7 GTP-Binding Proteins)
0 (rab7 GTP-binding proteins, human)
EC 3.6.5.2 (ADP-Ribosylation Factors)
EC 3.6.5.2 (rab GTP-Binding Proteins)

Date Created: 20200222 Date Completed: 20201109 Latest Revision: 20211204

20250114

PMC7073467

10.15252/embj.2019102301

32080880