Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation.
Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation.
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DOI：
10.1002/jev2.12311
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发表时间：
2023-03
影响因子：
16
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中科院分区：
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Exosome是一种分泌的纳米囊泡，具有强大的信号活性，最初在Rab7阳性的晚期多囊泡内小体中形成为腔内小泡(ILV)，在回收Rab11a阳性的内小体中也是如此，特别是在某些形式的营养胁迫下。运输所需的内体分选复合体(ESCRT)的核心蛋白参与外体的生物发生和ILV介导的泛素化货物的破坏。ESCRT-III辅助成分在ESCRT-III介导的囊泡断裂中的作用已有报道，但它们的确切功能尚不清楚。他们往往只在压力下才显得必不可少。对人细胞外小泡的比较蛋白质组学分析表明，在富含Rab11a的外切体制剂中，辅助ESCRT-III蛋白CHMP1A、CHMP1B、CHMP5和IST1增加。我们发现这些蛋白是在果蝇次级细胞循环内体中形成ILV所必需的，但与核心ESCRT不同的是，它们不参与晚期内体中泛素化蛋白的降解。此外，CHMP5在人HCT116结直肠癌细胞中被敲除，选择性地抑制Rab11a-exosome的产生。辅助性ESCRT-III基因敲除抑制了次级细胞的精液介导的生殖信号和来自HCT116细胞的含有Rab11a-exosome的EV的促生长活性。我们得出结论，ESCRT-III辅助成分在Rab11a-exosome的生成中具有特定的、泛素不依赖的作用，这一机制可能被靶向选择性地阻断癌症中这些囊泡的促肿瘤活性。
Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7‐positive multivesicular endosomes, and also in recycling Rab11a‐positive endosomes, particularly under some forms of nutrient stress. The core proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) participate in exosome biogenesis and ILV‐mediated destruction of ubiquitinylated cargos. Accessory ESCRT‐III components have reported roles in ESCRT‐III‐mediated vesicle scission, but their precise functions are poorly defined. They frequently only appear essential under stress. Comparative proteomics analysis of human small extracellular vesicles revealed that accessory ESCRT‐III proteins, CHMP1A, CHMP1B, CHMP5 and IST1, are increased in Rab11a‐enriched exosome preparations. We show that these proteins are required to form ILVs in Drosophila secondary cell recycling endosomes, but unlike core ESCRTs, they are not involved in degradation of ubiquitinylated proteins in late endosomes. Furthermore, CHMP5 knockdown in human HCT116 colorectal cancer cells selectively inhibits Rab11a‐exosome production. Accessory ESCRT‐III knockdown suppresses seminal fluid‐mediated reproductive signalling by secondary cells and the growth‐promoting activity of Rab11a‐exosome‐containing EVs from HCT116 cells. We conclude that accessory ESCRT‐III components have a specific, ubiquitin‐independent role in Rab11a‐exosome generation, a mechanism that might be targeted to selectively block pro‐tumorigenic activities of these vesicles in cancer.
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发表时间：
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期刊：
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影响因子：
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影响因子：
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