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.

中文翻译：

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四跨膜蛋白与外泌体的 ALIX 和 ESCRT-III 依赖性分选

内体的腔内囊泡 (ILV) 介导将激活的信号受体和其他蛋白质递送至溶酶体进行降解，但当它们作为外泌体分泌时，也可调节细胞间通讯。ILV的形成需要四种复合物：ESCRT-0、-I、-II和-III，其中ESCRT-0、-I和-II可能参与货物分类，ESCRT-III参与膜变形和裂变。在这里，我们报道了 ESCRT 相关蛋白 ALIX 的活性形式有效地将 ESCRT-III 蛋白招募到内体。这种募集独立于其他 ESCRT 发生，但体内需要溶双磷脂酸 (LBPA)，并且可以在体外在支持的双层上重建。我们的数据表明，这种 ALIX 和 ESCRT-III 依赖性途径促进了四跨膜蛋白向外泌体的分选和递送。我们得出的结论是，ALIX 提供了一条 ILV 形成的额外途径，继经典途径之后，并且该途径控制外泌体蛋白的靶向。