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During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1\u03b2 release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during<jats:italic>Yersinia<\/jats:italic>infection, we identified a line of<jats:italic>Card19<\/jats:italic>-deficient mice (<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>lxcn<\/jats:italic><\/jats:sup><jats:italic>)<\/jats:italic>whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as an independently-generated CRISPR\/Cas9<jats:italic>Card19<\/jats:italic>knockout mouse line (<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>Null<\/jats:italic><\/jats:sup>) showed no defect in macrophage cell lysis. Notably,<jats:italic>Card19<\/jats:italic>is located on chromosome 13, immediately adjacent to<jats:italic>Ninj1<\/jats:italic>, which was recently found to regulate cell lysis downstream of GSDMD activation. RNA-seq and western blotting revealed that<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>lxcn<\/jats:italic><\/jats:sup>BMDMs have significantly reduced NINJ1 expression, and reconstitution of<jats:italic>Ninj1<\/jats:italic>in<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>lxcn<\/jats:italic><\/jats:sup>immortalized BMDMs restored their ability to undergo cell lysis in response to caspase-dependent cell death stimuli.<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>lxcn<\/jats:italic><\/jats:sup>mice exhibited increased susceptibility to<jats:italic>Yersinia<\/jats:italic>infection, whereas independently-generated<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>Null<\/jats:italic><\/jats:sup>mice did not, demonstrating that cell lysis itself plays a key role in protection against bacterial infection, and that the increased infection susceptibility of<jats:italic>Card19<\/jats:italic><jats:sup><jats:italic>lxcn<\/jats:italic><\/jats:sup>mice is attributable to loss of NINJ1. Our findings identify genetic targeting of<jats:italic>Card19<\/jats:italic>being responsible for off-target effects on the adjacent gene<jats:italic>Ninj1<\/jats:italic>, disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during<jats:italic>Yersinia<\/jats:italic>infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009967","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T20:51:26Z","timestamp":1634244686000},"page":"e1009967","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-7699","authenticated-orcid":true,"given":"Elisabet","family":"Bjanes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyna 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