SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport
Jongsma, Marlieke Lm; Bakker, Jeroen; Cabukusta, Birol; Liv, Nalan; van Elsland, Daphne; Fermie, Job; Akkermans, Jimmy Ll; Kuijl, Coenraad; van der Zanden, Sabina Y; Janssen, Lennert; Hoogzaad, Denise; van der Kant, Rik; Wijdeven, Ruud H; Klumperman, Judith; Berlin, Ilana; Neefjes, Jacques
(2020) EMBO Journal, volume 39, issue 6, pp. 1 - 25
(Article)
Abstract
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
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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.
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Keywords: Arl8b, HOPS, Rab7, SKIP, TBC1D15, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, Molecular Biology, General Neuroscience, Journal Article
ISSN: 0261-4189
Publisher: Nature Publishing Group
Note: Funding Information: We thank S. Munro (MRC) for the generous gift of Arl8b-GFP and SKIP cDNA, as well as M. Seaman (CIMR) and T. Johansen (IMB) for kindly providing GFP-TBC1D5 and GFP-FYCO1 constructs, respectively. We thank R. Kim of the LUMC protein facility for help with secondary structure prediction in designing the SKIP truncation mutants, B. Koster for access to the LUMC electron microscopy facility, as well as L. Voortman and A. van der Laan-Boonzaier of the LUMC and L. Oomen and L. Brocks of the NKI for fluorescence microscopy facility support. We acknowledge technical assistance of the Cell Microscopy Core at the UMC Utrecht, especially C. de Heus. This work was supported by the NWO TOP and ERC Adv grants awarded to J. Neefjes. Publisher Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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