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The role of ISG15 during bacterial infection remains elusive. We show that ISG15 expression in nonphagocytic cells is dramatically induced upon Listeria infection. Surprisingly this induction can be type I interferon independent and depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection in vitro and in vivo. We made use of stable isotope labeling in tissue culture (SILAC) to identify ISGylated proteins that could be responsible for the protective effect. Strikingly, infection or overexpression of ISG15 leads to ISGylation of ER and Golgi proteins, which correlates with increased secretion of cytokines known to counteract infection. Together, our data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response.<\/jats:p>","DOI":"10.7554\/elife.06848","type":"journal-article","created":{"date-parts":[[2015,8,10]],"date-time":"2015-08-10T10:15:54Z","timestamp":1439201754000},"source":"Crossref","is-referenced-by-count":127,"title":["ISG15 counteracts Listeria monocytogenes infection"],"prefix":"10.7554","volume":"4","author":[{"given":"Lilliana","family":"Radoshevich","sequence":"first","affiliation":[{"name":"Unit\u00e9, Institut Pasteur, Paris, France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U604, Paris, France"},{"name":"Institut National de la Recherche Agronomique, USC2020, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Impens","sequence":"additional","affiliation":[{"name":"Unit\u00e9, Institut Pasteur, Paris, 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