Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198.
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093, CA.
Mol Biol Cell. 2024 Nov 1;35(11):ar144. doi: 10.1091/mbc.E24-07-0324. Epub 2024 Oct 9.
Endosome fission is required for the release of carrier vesicles and the recycling of receptors to the plasma membrane. Early events in endosome budding and fission rely on actin branching to constrict the endosomal membrane, ultimately leading to nucleotide hydrolysis and enzymatic fission. However, our current understanding of this process is limited, particularly regarding the coordination between the early and late steps of endosomal fission. Here we have identified a novel interaction between the endosomal scaffolding protein, MICAL-L1, and the human homologue of the Nervous Wreck (Nwk) protein, FCH and double SH3 domains protein 2 (FCHSD2). We demonstrate that MICAL-L1 recruits FCHSD2 to the endosomal membrane, where it is required for ARP2/3-mediated generation of branched actin, endosome fission and receptor recycling to the plasma membrane. Because MICAL-L1 first recruits FCHSD2 to the endosomal membrane, and is subsequently responsible for recruitment of the ATPase and fission protein EHD1 to endosomes, our findings support a model in which MICAL-L1 orchestrates endosomal fission by connecting between the early actin-driven and subsequent nucleotide hydrolysis steps of the process.
内体裂变对于载体囊泡的释放和受体向质膜的再循环是必需的。内体出芽和裂变的早期事件依赖于肌动蛋白分支来收缩内体膜，最终导致核苷酸水解和酶促裂变。然而，我们目前对这一过程的理解有限，特别是关于内体裂变的早期和晚期步骤之间的协调。在这里，我们发现了一种新型的内体支架蛋白 MICAL-L1 与 Nervous Wreck（Nwk）蛋白的人类同源物、FCH 和双 SH3 结构域蛋白 2（FCHSD2）之间的新相互作用。我们证明 MICAL-L1 将 FCHSD2 招募到内体膜上，这对于 ARP2/3 介导的分支肌动蛋白的产生、内体裂变和受体向质膜的再循环是必需的。因为 MICAL-L1 首先将 FCHSD2 招募到内体膜上，并且随后负责将 ATP 酶和分裂蛋白 EHD1 招募到内体中，所以我们的发现支持了这样一个模型，即 MICAL-L1 通过连接过程的早期肌动蛋白驱动和随后的核苷酸水解步骤来协调内体裂变。
