Abstract
Elongated tubular endosomes play essential roles in diverse cellular functions. Multiple molecules have been implicated in tubulation of recycling endosomes, but the mechanism of endosomal tubule biogenesis has remained unclear. In this study, we found that JRAB/MICAL-L2 induces endosomal tubulation via activated Rab8A. In association with Rab8A, JRAB/MICAL-L2 adopts its closed form, which functions in the tubulation of recycling endosomes. Moreover, JRAB/MICAL-L2 induces liquid–liquid phase separation, initiating the formation of tubular recycling endosomes upon overexpression. Between its N-terminal and C-terminal globular domains, JRAB/MICAL-L2 contains an intrinsically disordered region, which contributes to the formation of JRAB/MICAL-L2 condensates. Based on our findings, we propose that JRAB/MICAL-L2 plays two sequential roles in the biogenesis of tubular recycling endosomes: first, JRAB/MICAL-L2 organizes phase separation, and then the closed form of JRAB/MICAL-L2 formed by interaction with Rab8A promotes endosomal tubulation.
Highlights
Elongated tubular endosomes play essential roles in diverse cellular functions
We propose a new model in which JRAB/MICAL-L2 adopts its closed form through association with Rab8A, and that the JRAB/MICAL-L2–Rab8A complex is involved in endosomal tubulation
We propose that two kinds of Rab proteins fulfill their individual functions through a conformational change of their common effector in the corresponding sites within the cell
Summary
Elongated tubular endosomes play essential roles in diverse cellular functions. Multiple molecules have been implicated in tubulation of recycling endosomes, but the mechanism of endosomal tubule biogenesis has remained unclear. In association with Rab8A, JRAB/MICAL-L2 adopts its closed form, which functions in the tubulation of recycling endosomes. JRAB/MICAL-L2 induces liquid–liquid phase separation, initiating the formation of tubular recycling endosomes upon overexpression. We propose that JRAB/MICAL-L2 plays two sequential roles in the biogenesis of tubular recycling endosomes: first, JRAB/MICAL-L2 organizes phase separation, and the closed form of JRAB/MICAL-L2 formed by interaction with Rab8A promotes endosomal tubulation. There are two different kinds of endocytic recycling pathways: fast recycling via a direct route from early endosomes, and slow recycling via an indirect route through the endocytic recycling compartment (ERC) In the latter type of recycling, dynamics of tubular endosomes have crucial roles in more efficient and reliable transport of cargo to the cell surface. When determining the cellular function of a Rab protein, we must first identify its effector protein
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