Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, 250021, Jinan, Shandong, China.
Department of Neurology, Dongying People's Hospital, 257091, Dongying, Shandong, China.
Nat Commun. 2019 Apr 9;10(1):1639. doi: 10.1038/s41467-019-09720-x.
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.
外泌体是细胞融合多泡体（MVB）与质膜（PM）后释放的纳米大小的膜囊泡，在细胞间通讯和许多生物过程中发挥重要作用。然而，调节外泌体分泌的分子机制仍知之甚少。在这里，我们将 KIBRA 鉴定为一种衔接子样蛋白，它稳定 Rab27a，进而控制体外和体内的外泌体分泌。在神经元和足细胞系中敲低或过表达 KIBRA 分别导致外泌体分泌减少或增加，并且 KIBRA 耗竭会增加 MVB 的大小和数量。比较 KIBRA 敲除和野生型小鼠大脑的蛋白质谱显示，Rab27a，一种调节 MVB-PM 对接的小 GTPase，显著减少。Rab27a 通过与 KIBRA 相互作用而稳定，这可防止通过泛素蛋白酶体途径进行泛素化和降解。总之，我们表明 KIBRA 通过抑制 Rab27a 的蛋白酶体降解来控制外泌体分泌。
Zotero 插件
