澳大利亚国立大学Si Ming Man课题组发现，炎性小体蛋白在肿瘤发展过程中作为DNA损伤复合体的支架。2024年10月14日，《自然—免疫学》杂志在线发表了这项成果。

研究人员表明，炎性小体蛋白NLR家族CARD结构域蛋白4（NLRC4）在Apc^min/+小鼠模型中抑制了肿瘤的发生。这一反应与NLRP3、NLRP6、NLR家族凋亡抑制蛋白、黑色素瘤缺失蛋白2、含有凋亡相关斑点样蛋白的半胱氨酸蛋白酶募集结构域、半胱氨酸蛋白酶-1和半胱氨酸蛋白酶-11的炎症小体信号无关。

NLRC4与DNA损伤感知蛋白复合体相互作用，包括共激活蛋白ATR、ATR相互作用蛋白（ATRIP）和Ewing瘤相关抗原1（ETAA1）。然后促进检查点适配蛋白claspin的招募，从而激活激酶检查点蛋白1（CHK1）。

基因毒性诱导的NLRC4–ATR–ATRIP–ETAA1复合体的激活推动了肿瘤抑制DNA损伤反应和CHK1的激活，并进一步减轻了DNA损伤的累积。这些发现表明炎性小体蛋白在促进DNA损伤反应和抗癌保护中的一种非炎症功能。

据介绍，炎症传感器激活细胞信号机制，推动炎症和细胞死亡过程。此外，炎性小体还通过独立于其传统功能的方式调控某些疾病的发展。

附：英文原文

Title: Inflammasome protein scaffolds the DNA damage complex during tumor development

Author: Shen, Cheng, Pandey, Abhimanu, Enosi Tuipulotu, Daniel, Mathur, Anukriti, Liu, Lixinyu, Yang, Haoyu, Adikari, Nilanthi K., Ngo, Chinh, Jing, Weidong, Feng, Shouya, Hao, Yuwei, Zhao, Anyang, Kirkby, Max, Kurera, Melan, Zhang, Jing, Venkataraman, Shweta, Liu, Cheng, Song, Renhua, Wong, Justin J.-L., Schumann, Ulrike, Natoli, Riccardo, Wen, Jiayu, Zhang, Liman, Kaakoush, Nadeem O., Man, Si Ming

Issue&Volume: 2024-10-14

Abstract: 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 Apcmin/+ 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.

DOI: 10.1038/s41590-024-01988-6

Source: https://www.nature.com/articles/s41590-024-01988-6