![]() JRAB/MICAL-L2–Rab8A localizes in a perinuclear compartment (probably the ERC) and regulates the recycling of E-cadherin, whereas JRAB/MICAL-L2–Rab13 localizes underneath the plasma membrane and regulates the formation of tight junctions via the recycling of claudins and occludin 8, 16. Thus, when determining the cellular function of a Rab protein, we must first identify its effector protein. GTP-bound Rab interacts with specific proteins, called effector proteins, and the Rab–effector protein complex provides each Rab with a specific function 15. Each Rab protein exchanges between its GTP-bound active form and GDP-bound inactive form. Each Rab protein localizes on a distinct membrane organelle or plasma membrane, and then regulates the transport of proteins or lipids there. ![]() In mammalian cells, the Rab family consists of more than 70 members. Small GTPases of the Rab family are involved in the regulation of membrane trafficking 9, 10, 11, 12, 13, 14. In a previous study, we identified JRAB/MICAL-L2 as an effector protein for Rab8A and Rab13, as well as MICAL-L1 8. They contain calponin homology (CH), LIM, and coiled-coil (CC) domains, and MICAL-1, MICAL-2, and MICAL-3 also possess a flavin adenine dinucleotide-binding monooxygenase domain. MICAL proteins are large, multidomain, cytosolic proteins expressed in specific neuronal and non-neuronal cells both during development and in adulthood. MICAL-L1 belongs to the MICAL family, which has four other members in mammals: MICAL-1, MICAL-2, MICAL-3, and JRAB/MICAL-L2 7. However, the mechanism of endosomal tubule biogenesis has remained unclear. In addition, recent studies showed that MICAL-L1 and syndapin2 localize on tubular recycling endosomes via phosphatidic acid (PA), leading to the initiation of endosomal tubulation 6. Several key regulatory proteins involved in the formation and maintenance of endosomal tubules have been discovered, including the small GTPases Rab8, Rab10, and Rab35, Arf6, Eps15 homology domain protein 1 (EHD-1), syndapin2 (an F-BAR protein), and MICAL-L1, which acts as a hub connecting the other factors 2, 3, 4, 5. Thus, cargos may travel safely over a long distance via a specific structure, i.e., the elongated tubular endosome. First, cargos on the tips of elongated tubular endosome approach their destination, and are then separated from the tube as vesicles. ![]() 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. 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). Various cell-surface proteins, including transmembrane receptors and lipids, are internalized and return to the plasma membrane via endocytic recycling. ![]() 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.ĭuring fundamental cellular processes such as cell adhesion, migration, cell polarity, and signal transduction, the endocytic recycling pathways have a pivotal role in organizing the surface area and composition of the plasma membrane 1. 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. Moreover, JRAB/MICAL-L2 induces liquid–liquid phase separation, initiating the formation of tubular recycling endosomes upon overexpression. ![]() In association with Rab8A, JRAB/MICAL-L2 adopts its closed form, which functions in the tubulation of recycling endosomes. In this study, we found that JRAB/MICAL-L2 induces endosomal tubulation via activated Rab8A. Multiple molecules have been implicated in tubulation of recycling endosomes, but the mechanism of endosomal tubule biogenesis has remained unclear. Elongated tubular endosomes play essential roles in diverse cellular functions. ![]()
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