State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
J Extracell Vesicles. 2024 Jul;13(7):e12494. doi: 10.1002/jev2.12494.
Microvesicles (MVs) containing proteins, nucleic acid or organelles are shed from the plasma membrane. Although the mechanisms of MV budding are well elucidated, the connection between endosomal trafficking and MV formation remains poorly understood. In this report, RAB22A is revealed to be crucial for EGFR-containing MVs formation by the RAB GTPase family screening. RAB22A recruits TBC1D2B, a GTPase-activating protein (GAP) of RAB7A, to inactivate RAB7A, thus preventing EGFR from being transported to late endosomes and lysosomes. RAB22A also engages SH3BP5L, a guanine-nucleotide exchange factor (GEF) of RAB11A, to activate RAB11A on early endosomes. Consequently, EGFR is recycled to the cell surface and packaged into MVs. Furthermore, EGFR can phosphorylate RAB22A at Tyr136, which in turn promotes EGFR-containing MVs formation. Our findings illustrate that RAB22A acts as a sorter on early endosomes to sort EGFR to recycling endosomes for MV shedding by both activating RAB11A and inactivating RAB7A.
微泡（MVs）含有蛋白质、核酸或细胞器，从质膜脱落。尽管 MV 出芽的机制已被充分阐明，但内体运输与 MV 形成之间的联系仍知之甚少。在本报告中，通过 RAB GTPase 家族筛选发现 RAB22A 对于含 EGFR 的 MV 形成至关重要。RAB22A 招募 TBC1D2B，即 RAB7A 的 GTPase 激活蛋白（GAP），使其失活，从而阻止 EGFR 被运送到晚期内体和溶酶体。RAB22A 还与 SH3BP5L 结合，后者是 RAB11A 的鸟嘌呤核苷酸交换因子（GEF），从而在早期内体上激活 RAB11A。因此，EGFR 被回收至细胞表面并包装到 MV 中。此外，EGFR 可在 Tyr136 处磷酸化 RAB22A，这反过来又促进含 EGFR 的 MV 形成。我们的研究结果表明，RAB22A 作为早期内体上的分选器，通过激活 RAB11A 和失活 RAB7A 将 EGFR 分选至再循环内体以进行 MV 脱落。
