Inflammasome 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.

炎性小体传感器激活细胞信号机制以驱动炎症和细胞死亡过程。炎性小体还独立于典型功能控制某些疾病的发展。在这里，我们表明炎性小体蛋白 NLR 家族 CARD 结构域包含蛋白 4 （NLRC4） 减轻了 Apc^min/+ 小鼠模型中肿瘤的发展。这种反应独立于 NLRP3 、 NLRP6 、 NLR 家族凋亡抑制蛋白的炎性小体信号传导，黑色素瘤 2 中不存在，凋亡相关斑点样蛋白含有 caspase 募集结构域、 caspase-1 和 caspase-11。NLRC4 与 DNA 损伤感应性共济失调毛细血管扩张症和 Rad3 相关 （ATR）-ATR 相互作用蛋白 （ATRIP）-尤文肿瘤相关抗原 1 （ETAA1） 复合物相互作用，促进检查点接头蛋白桥接蛋白的募集，开启激酶检查点激酶-1 （CHK1） 的激活。遗传毒性诱导的 NLRC4-ATR-ATRIP-ETAA1 复合物激活驱动肿瘤抑制 DNA 损伤反应和 CHK1 激活，并进一步减轻 DNA 损伤的积累。这些发现表明，炎性小体蛋白在促进 DNA 损伤反应和介导对癌症的保护方面具有非炎症功能。