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KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.

ABSTRACT: 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.

SUBMITTER: Song L

PROVIDER: S-EPMC6456494 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.

Song Lin L Tang Shi S Han Xiaolei X Jiang Ziying Z Dong Lingling L Liu Cuicui C Liang Xiaoyan X Dong Jixin J Qiu Chengxuan C Wang Yongxiang Y Du Yifeng Y

Nature communications 20190409 1

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 ne ...[more]

PMID: 30967557

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Project description:Exosomes are small membrane-bound vesicles which are intraluminal vesicles (ILVs) secreted to the extracellular space after multivesicular bodies (MVBs) fuse with the plasma membrane. Although it is known that exosomes play a multitude of roles during viral infection, the mechanism that regulates their secretion during viral infection is unknown. Here, we found that enterovirus A71 (EV-A71) infection increased exosome secretion both in vivo and in vitro. Importantly, the expression of nonstructural protein 3A was sufficient to promote exosome secretion, while a mutation affecting the amino acid 18 position abrogated this effect, without changing the size of exosomes in vivo or in vitro. Transmission electron microscopy (TEM) analysis revealed that 3A decreases the number of MVBs and ILVs in vivo and in vitro, which suggested 3A may boost the fusion between MVBs and the plasma membrane. Furthermore, we demonstrated that an interaction between 3A and the small GTPase protein, Rab27a, protected Rab27a from ubiquitination, resulted in increasing exosome release. Data indicated a novel mechanism by which EV-A71 3A modifies exosome secretion during viral infection. IMPORTANCE Research has shown that viral infection impacts exosome secretion, but its regulation mechanisms remain poorly understood. Nonstructural protein 3A of EV-A71 interacts with many host factors and is involved in the remodeling of cellular membranes. In this investigation, we applied exogenous expression of 3A protein for exploring its regulation on exosome secretion and utilized immunoprecipitation combined with proteomics approaches to identify 3A-interacting factors. Our results demonstrate that 3A protein upregulates the release of the exosomes and that the 3A mutant strain of EV-A71 induce less exosome release compared with the EV-A71 wild type. Viral 3A protein interacts with the host factor Rab27a to prevent it from being ubiquitinated, which in turn improves exosome secretion both in vitro and in vivo. EV-A71 3A protein is a novel viral factor in the control of exosome production.

Dataset Information

KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.

Publications

KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.

Similar Datasets

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