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The IFN\u03b3 receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFN\u03b3-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery,\n                    <jats:italic>Shigella flexneri<\/jats:italic>\n                    , uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213.\n                    <jats:italic>S. flexneri<\/jats:italic>\n                    mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFN\u03b3-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of\n                    <jats:italic>S. flexneri<\/jats:italic>\n                    requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of\n                    <jats:italic>S. flexneri<\/jats:italic>\n                    is insufficient to kill intracellular bacteria, suggesting that\n                    <jats:italic>S. flexneri<\/jats:italic>\n                    employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen\n                    <jats:italic>Shigella<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.7554\/elife.102714","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T10:25:07Z","timestamp":1732098307000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102714","source":"Crossref","is-referenced-by-count":9,"title":["The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4362-8928","authenticated-orcid":true,"given":"Luz","family":"Saavedra-Sanchez","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center","place":["Durham, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7227-9640","authenticated-orcid":true,"given":"Mary 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