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oai:repisalud.isciii.es:20.500.12105/51742024-09-27T08:49:57Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Villarroya-Beltri, Carolina author Baixauli, Francesc author Mittelbrunn, Maria author Fernandez-Delgado, Irene author Torralba, Daniel author Moreno-Gonzalo, Olga author Baldanta, Sara author Enrich, Carlos author Guerra, Susana author Sanchez-Madrid, Francisco author 2016 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. Nat Commun. 2016; 7:13588 10.1038/ncomms13588 2041-1723 NATURE COMMUNICATIONS 27882925 http://hdl.handle.net/20.500.12105/5174 UBIQUITIN-LIKE PROTEIN MULTIVESICULAR BODY FORMATION INTERFERON-STIMULATED GENE HUMAN-CELLS AUTOPHAGIC VACUOLES MEMBRANE-PROTEINS ISG15 CONJUGATION VIRAL RESISTANCE PLASMA-MEMBRANE LIGASE ACTIVITY ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins