Department of Biochemistry, Université de Genève, Geneva, Switzerland.
J Cell Biol. 2020 Mar 2;219(3). doi: 10.1083/jcb.201904113.
The intraluminal vesicles (ILVs) of endosomes mediate the delivery of activated signaling receptors and other proteins to lysosomes for degradation, but they also modulate intercellular communication when secreted as exosomes. The formation of ILVs requires four complexes, ESCRT-0, -I, -II, and -III, with ESCRT-0, -I, and -II presumably involved in cargo sorting and ESCRT-III in membrane deformation and fission. Here, we report that an active form of the ESCRT-associated protein ALIX efficiently recruits ESCRT-III proteins to endosomes. This recruitment occurs independently of other ESCRTs but requires lysobisphosphatidic acid (LBPA) in vivo, and can be reconstituted on supported bilayers in vitro. Our data indicate that this ALIX- and ESCRT-III-dependent pathway promotes the sorting and delivery of tetraspanins to exosomes. We conclude that ALIX provides an additional pathway of ILV formation, secondary to the canonical pathway, and that this pathway controls the targeting of exosomal proteins.
内体小泡（ILVs）介导激活的信号受体和其他蛋白质向溶酶体的输送以进行降解，但当作为外泌体分泌时，它们也调节细胞间通讯。ILVs 的形成需要四个复合物，ESCRT-0、-I、-II 和 -III，其中 ESCRT-0、-I 和 -II 可能参与货物分拣，而 ESCRT-III 则参与膜变形和分裂。在这里，我们报告说，ESCRT 相关蛋白 ALIX 的一种活性形式可有效地将 ESCRT-III 蛋白募集到内体上。这种募集发生在其他 ESCRTs 之外，但需要体内的溶血磷脂酸（LBPA），并且可以在体外的支持双层膜上重建。我们的数据表明，这种依赖于 ALIX 和 ESCRT-III 的途径促进了四跨膜蛋白向外泌体的分拣和输送。我们得出结论，ALIX 提供了 ILV 形成的另一种途径，是经典途径的补充，并且该途径控制着外泌体蛋白的靶向。
