期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms13588
关键词
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资金
- Spanish Ministry of Economy and Competitiveness [SAF2014-55579-R, BFU2015-66785-P]
- Comunidad de Madrid [INDISNET-S2011/BMD-2332]
- Cardiovascular Network from Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III) [RD12-0042-0056, PIE13/00041]
- Fondo Europeo de Desarrollo Regional FEDER
- COST-Action [BM1202]
- FIS (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III) [PI11/00127]
- FIS (Ministry of Health of Spain, State secretary of R+D) [PI11/00127]
- FIS (FEDER/FSE)
- Bayer Group Grants4Grants [2013-08-0982]
- Spanish Ministry of Economy and Competitiveness (MINECO)
- Pro-CNIC Foundation
- Severo Ochoa Center of Excellence (MINECO) [SEV-2015-0505]
- FPU programme (Spanish Ministry of Education)
- Instituto de Salud Carlos III [MS14/00219]
- [ERC-2011-AdG 294340-GENTRIS]
- [SAF2014-54623-R]
Exosomes are vesicles secreted to the extracellular environment through fusion with the plasma membrane of specific endosomes called multivesicular bodies (MVB) and mediate cell-to-cell communication in many biological processes. Posttranslational modifications are involved in the sorting of specific proteins into exosomes. Here we identify ISGylation as a ubiquitin-like modification that controls exosome release. ISGylation induction decreases MVB numbers and impairs exosome secretion. Using ISG15-knockout mice and mice expressing the enzymatically inactive form of the de-ISGylase USP18, we demonstrate in vitro and in vivo that ISG15 conjugation regulates exosome secretion. ISG15 conjugation triggers MVB co-localization with lysosomes and promotes the aggregation and degradation of MVB proteins. Accordingly, inhibition of lysosomal function or autophagy restores exosome secretion. Specifically, ISGylation of the MVB protein TSG101 induces its aggregation and degradation, being sufficient to impair exosome secretion. These results identify ISGylation as a novel ubiquitin-like modifier in the control of exosome production.
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