Division of Membrane Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan.
J Cell Sci. 2019 Oct 3;132(19):jcs229179. doi: 10.1242/jcs.229179.
Ubiquitinated membrane proteins such as epidermal growth factor receptor (EGFR) are delivered to early endosomes and then sorted to lysosomes via multivesicular bodies (MVBs) for degradation. The regulatory mechanism underlying formation of intralumenal vesicles en route to generation of MVBs is not fully understood. In this study, we found that SH3YL1, a phosphoinositide-binding protein, had a vesicular localization pattern overlapping with internalized EGF in endosomes in the degradative pathway. Deficiency of SH3YL1 prevents EGF trafficking from early to late endosomes and inhibits degradation of EGFR. Moreover, we show that SH3YL1 mediates EGFR sorting into MVBs in a manner dependent on its C-terminal SH3 domain, which is necessary for the interaction with an ESCRT-I component, Vps37B. Taken together, our observations reveal an indispensable role of SH3YL1 in MVB sorting and EGFR degradation mediated by ESCRT complexes.
泛素化的膜蛋白，如表皮生长因子受体（EGFR），被递送至早期内体，然后通过多泡体（MVB）分选至溶酶体进行降解。MVB 形成过程中管腔内囊泡形成的调节机制尚未完全阐明。在这项研究中，我们发现 SH3YL1，一种磷酸肌醇结合蛋白，其囊泡定位模式与降解途径中内体中内化的 EGF 重叠。SH3YL1 的缺乏会阻止 EGF 从早期内体向晚期内体的运输，并抑制 EGFR 的降解。此外，我们表明 SH3YL1 以依赖其 C 末端 SH3 结构域的方式将 EGFR 分选到 MVB 中，该结构域对于与 ESCRT-I 成分 Vps37B 的相互作用是必需的。总之，我们的观察结果揭示了 SH3YL1 在 ESCRT 复合物介导的 MVB 分选和 EGFR 降解中的不可或缺的作用。
