Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Immunol. 2022 Jun;23(6):916-926. doi: 10.1038/s41590-022-01199-x. Epub 2022 May 26.
At steady state, the NOD-like receptor (NLR)-containing pyrin domain (PYD) (NLRP)1 inflammasome is maintained in an auto-inhibitory complex by dipeptidyl peptidases 8 and 9 (DPP8 and DPP9) and is activated by pathogen-encoded proteases after infection. Here, we showed that the open reading frame (ORF)45 protein of the Kaposi's sarcoma-associated herpesvirus activated the human NLRP1 (hNLRP1) inflammasome in a non-protease-dependent manner, and we additionally showed that the Linker1 region of hNLRP1, situated between the PYD and NACHT domains, was required for the auto-inhibition and non-protease-dependent activation of hNLRP1. At steady state, the interaction between Linker1 and the UPA subdomain silenced the activation of hNLRP1 in auto-inhibitory complexes either containing DPP9 or not in a manner independent of DPP9. ORF45 binding to Linker1 displaced UPA from the Linker1-UPA complex and induced the release of the C-terminal domain of hNLRP1 for inflammasome assembly. The ORF45-dependent activation of the NLRP1 inflammasome was conserved in primates but was not observed for murine NLRP1b inflammasomes.
在稳定状态下，含核苷酸结合寡聚化结构域（NOD）样受体（NLR）-富含吡喃结构域（PYD）（NLRP）1 炎性小体被二肽基肽酶 8 和 9（DPP8 和 DPP9）维持在自身抑制复合物中，并在感染后被病原体编码的蛋白酶激活。在这里，我们表明卡波济肉瘤相关疱疹病毒的开放阅读框（ORF）45 蛋白以非蛋白酶依赖的方式激活人类 NLRP1（hNLRP1）炎性小体，并且我们还表明 hNLRP1 的 Linker1 区域，位于 PYD 和 NACHT 结构域之间，是 hNLRP1 的自身抑制和非蛋白酶依赖激活所必需的。在稳定状态下，Linker1 与 UPA 亚结构域之间的相互作用以不依赖 DPP9 的方式沉默了含有或不含有 DPP9 的自身抑制复合物中 hNLRP1 的激活。ORF45 与 Linker1 的结合将 UPA 从 Linker1-UPA 复合物中置换出来，并诱导 hNLRP1 的 C 末端结构域释放以进行炎性小体组装。NLRP1 炎性小体的 ORF45 依赖性激活在灵长类动物中是保守的，但在鼠类 NLRP1b 炎性小体中未观察到。
