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 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.
Highlights
The endolysosomal system consists of a dynamic network of vesicular structures working together to achieve controlled uptake and proteolysis of materials derived from the extracellular space.Regulated transport and sorting of cargoes along the endocytic route enable cells to effectively interpret and mitigate extracellular cues (Sigismund et al, 2012; Bakker et al, 2017), fight off pathogens (Gruenberg & van der Goot, 2006; Roche & Furuta, 2015) and sustain homeostasis (Lim & Zoncu, 2016)
To study transport route selectivity operational on endolysosomes, we examined the interplay between their associated GTPases, Rab7, and Arl8b
It has been speculated that Arl8b marks a later maturation stage as compared to Rab7 (Hofmann & Munro, 2006; Garg et al, 2011), and we considered whether Rab7 activity status affects localization and behaviour of Arl8b
Summary
The endolysosomal system consists of a dynamic network of vesicular structures working together to achieve controlled uptake and proteolysis of materials derived from the extracellular space.Regulated transport and sorting of cargoes along the endocytic route enable cells to effectively interpret and mitigate extracellular cues (Sigismund et al, 2012; Bakker et al, 2017), fight off pathogens (Gruenberg & van der Goot, 2006; Roche & Furuta, 2015) and sustain homeostasis (Lim & Zoncu, 2016). To ensure order within this vesicular network and regulate access to the proteolytic compartment, the endolysosomal system is compartmentalized in cellular space (Neefjes et al, 2017). Once nascent endosomes are acquired in the cell periphery, they undergo progressive maturation through controlled interactions with late compartments (Huotari & Helenius, 2011). This process of maturation is accompanied by ordered transitions in membrane identity (Cullen & Carlton, 2012), coupled to sequestration of cargoes marked for destruction onto intraluminal vesicles (ILVs; Christ et al, 2017). We explore one aspect of this complexity by dissecting how changes in endolysosomal membrane identity are coupled to choice(s) of transport route
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