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Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxin released by P. aeruginosa type 2 secretion system (T2SS), during chronic infection. Mechanistically, EXOA-driven eukaryotic elongation factor 2 (EEF2) ribosylation and covalent inactivation promote ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, diphtheria toxin and cholix toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress\u2013associated kinases ZAK\u03b1- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, cystic fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress\u2013dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAK\u03b1 inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAK\u03b1 as a critical sensor of virulence-inactivated EEF2.<\/jats:p>","DOI":"10.1084\/jem.20230104","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T02:21:01Z","timestamp":1689387661000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4317-7706","authenticated-orcid":true,"given":"Miriam","family":"Pinilla","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016zvc994","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pharmacology and Structural Biology 1 , Toulouse, France"},{"name":", University of Toulouse, CNRS 1 , 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