KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a
KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a
复制标题
KIBRA 通过抑制 Rab27a 的蛋白酶体降解来控制外泌体分泌
DOI：
10.1038/s41467-019-09720-x
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发表时间：
2019-04-09
影响因子：
16.6
通讯作者：
Du, Yifeng
中科院分区：
文献类型：
--
作者：
Song, Lin;Tang, Shi;Du, Yifeng
外泌体是多泡体（MVB）与质膜（PM）融合后从细胞释放的纳米级膜囊泡，并且在细胞间通讯和许多生物过程中起重要作用。然而，调节外泌体分泌的分子机制仍然知之甚少。在这里，我们确定KIBRA作为一个衔接子样蛋白，稳定Rab 27 a，这反过来控制外泌体分泌在体外和体内。KIBRA在神经元和足细胞系中的敲低或过表达分别导致外泌体分泌的减少或增加，并且KIBRA消耗增加MVB大小和数量。比较KIBRA敲除和野生型小鼠脑之间的蛋白质谱显示Rab 27 a显著降低，Rab 27 a是一种调节MVB-PM对接的小GTdR。Rab 27 a通过与KIBRA相互作用而稳定，KIBRA通过泛素-蛋白酶体途径阻止泛素化和降解。总之，我们表明KIBRA通过抑制Rab 27 a的蛋白酶体降解来控制外泌体分泌。
Exosomes are nanosized membrane vesicles released from cells after fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) and play important roles in intercellular communication and numerous biological processes. However, the molecular mechanisms regulating exosome secretion remain poorly understood. Here we identify KIBRA as an adaptor-like protein that stabilizes Rab27a, which in turn controls exosome secretion both in vitro and in vivo. Knockdown or overexpression of KIBRA in neuronal and podocyte cell lines leads to a decrease or increase of exosome secretion, respectively, and KIBRA depletion increases MVB size and number. Comparing protein profiles between KIBRA knockout and wild-type mouse brain showed significantly decreased Rab27a, a small GTPase that regulates MVB-PM docking. Rab27a is stabilized by interacting with KIBRA, which prevents ubiquitination and degradation via the ubiquitin-proteasome pathway. In conclusion, we show that KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.