Shen, ChengPandey, AbhimanuTuipulotu, Daniel EnosiMathur, AnukritiLiu, LixinyuYang, HaoyuAdikari, Nilanthi K.Ngo, ChinhJing, WeidongFeng, ShouyaHao, YuweiZhao, AnyangKirkby, MaxKurera, MelanZhang, JingVenkataraman, ShwetaLiu, ChengSong, RenhuaWong, Justin J. -L.Schumann, UlrikeNatoli, RiccardoWen, JiayuZhang, LimanKaakoush, Nadeem O.Man, Si Ming2025-06-302025-06-301529-2908WOS:001331106800002PubMed:39402152ORCID:/0000-0002-2367-3422/work/185261264ORCID:/0000-0002-9350-0439/work/185261378ORCID:/0000-0002-5079-2857/work/185261459ORCID:/0000-0002-2379-1226/work/185261863http://www.scopus.com/inward/record.url?scp=85206828671&partnerID=8YFLogxKhttps://hdl.handle.net/1885/733765854Inflammasome sensors activate cellular signaling machineries to drive inflammation and cell death processes. Inflammasomes also control the development of certain diseases independently of canonical functions. Here, we show that the inflammasome protein NLR family CARD domain-containing protein 4 (NLRC4) attenuated the development of tumors in the Apc min/+ mouse model. This response was independent of inflammasome signaling by NLRP3, NLRP6, NLR family apoptosis inhibitory proteins, absent in melanoma 2, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1 and caspase-11. NLRC4 interacted with the DNA-damage-sensing ataxia telangiectasia and Rad3-related (ATR)–ATR-interacting protein (ATRIP)–Ewing tumor-associated antigen 1 (ETAA1) complex to promote the recruitment of the checkpoint adapter protein claspin, licensing the activation of the kinase checkpoint kinase-1 (CHK1). Genotoxicity-induced activation of the NLRC4–ATR–ATRIP–ETAA1 complex drove the tumor-suppressing DNA damage response and CHK1 activation, and further attenuated the accumulation of DNA damage. These findings demonstrate a noninflammatory function of an inflammasome protein in promoting the DNA damage response and mediating protection against cancer.We thank the facilities and scientific and technical assistance of Microscopy Australia at the Centre for Advanced Microscopy (ANU), which is funded by the University and the Federal Government. We thank the National Collaborative Research Infrastructure Strategy (NCRIS) via Phenomics Australia. We thank the South Australian Genomics Centre (SAGC), which is supported by NCRIS via BioPlatforms Australia and by the SAGC partner institutes. We thank the facilities and scientific and technical assistance of the Cytometry, Histology and Spatial Multiomics facility of the John Curtin School of Medical Research, ANU. We thank G. Burgio (ANU) for generating the Nlrp6 \u2212/\u2212 mice, R. E. Vance and E. Turcotte (University of California) for providing the WT and NLRC4 \u2212/\u2212 THP-1 cell lines, and J.-W. Yu (Yonsei University College of Medicine) for providing the anti-NLRC4 antibody. We thank members of the Man laboratory for their comments and suggestions; the National Health and Medical Research Council of Australia under project grant no. APP1146864, an ideas grant no. APP2002686 and an investigator grant no. 2026910 (S.M.M.); a CSL Centenary Fellowship (S.M.M.); a John Curtin School of Medical Research PhD Scholarship (C.S.); the Gretel and Gordon Bootes Medical Research Foundation (C.S.); a Cancer Council ACT Research Grant (A.M.); a Gastroenterological Society of Australia GESA Mostyn Family Grant (D.E.T.); and an Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems grant no. CE230100001 (L.L., H.Y., J.W.). We thank the facilities and scientific and technical assistance of Microscopy Australia at the Centre for Advanced Microscopy (ANU), which is funded by the University and the Federal Government. We thank the National Collaborative Research Infrastructure Strategy (NCRIS) via Phenomics Australia. We thank the South Australian Genomics Centre (SAGC), which is supported by NCRIS via BioPlatforms Australia and by the SAGC partner institutes. We thank the facilities and scientific and technical assistance of the Cytometry, Histology and Spatial Multiomics facility of the John Curtin School of Medical Research, ANU. We thank G. Burgio (ANU) for generating the Nlrp6 mice, R. E. Vance and E. Turcotte (University of California) for providing the WT and NLRC4 THP-1 cell lines, and J.-W. Yu (Yonsei University College of Medicine) for providing the anti-NLRC4 antibody. We thank members of the Man laboratory for their comments and suggestions; the National Health and Medical Research Council of Australia under project grant no. APP1146864, an ideas grant no. APP2002686 and an investigator grant no. 2026910 (S.M.M.); a CSL Centenary Fellowship (S.M.M.); a John Curtin School of Medical Research PhD Scholarship (C.S.); the Gretel and Gordon Bootes Medical Research Foundation (C.S.); a Cancer Council ACT Research Grant (A.M.); a Gastroenterological Society of Australia GESA Mostyn Family Grant (D.E.T.); and an Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems grant no. CE230100001 (L.L., H.Y., J.W.).35en© 2024 The Author(s)Multiple intestinal neoplasiaInnate immune recognitionGamma-inducing factorBacterial ligandsGasdermin-dCell-deathCauses autoinflammationActivates caspase-1Nlrc4 causesInterleukin-1-beta202410.1038/s41590-024-01988-685206828671