Endocytosis blocks the vesicular secretion of exosome marker proteins

作者：Yiwei Ai, Chenxu Guo, Marta García-Contreras, Laura S. Sánchez B., András Saftics, Oluwapelumi Shodubi, Shankar Raghunandan, Junhao Xu, Shang Jui Tsai, Yi Dong, Rong Li, Tijana Jovanović‐Talisman, Stephen J. Gould · 发表于：Science Advances · 年份：2024 · DOI：10.1126/sciadv.adi9156 · 被引用次数：67 · 研究领域：Extracellular vesicles in disease、RNA Interference and Gene Delivery、Lipid Membrane Structure and Behavior

Exosomes are secreted vesicles of ~30 to 150 nm diameter that play important roles in human health and disease. To better understand how cells release these vesicles, we examined the biogenesis of the most highly enriched human exosome marker proteins, the exosomal tetraspanins CD81, CD9, and CD63. We show here that endocytosis inhibits their vesicular secretion and, in the case of CD9 and CD81, triggers their destruction. Furthermore, we show that syntenin, a previously described exosome biogenesis factor, drives the vesicular secretion of CD63 by blocking CD63 endocytosis and that other endocytosis inhibitors also induce the plasma membrane accumulation and vesicular secretion of CD63. Finally, we show that CD63 is an expression-dependent inhibitor of endocytosis that triggers the vesicular secretion of lysosomal proteins and the clathrin adaptor AP-2 mu2. These results suggest that the vesicular secretion of exosome marker proteins in exosome-sized vesicles occurs primarily by an endocytosis-independent pathway.