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，含有热蛋白结构域 (PYD) (NLRP)1 的 NOD 样受体 (NLR) 炎症小体由二肽基肽酶 8 和 9（DPP8 和 DPP9）维持在自抑制复合物中，并被病原体编码的感染后的蛋白酶。在这里，我们表明卡波西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性方式激活人NLRP1（hNLRP1）炎症小体，并且我们还表明hNLRP1的Linker1区域位于hNLRP1 的自动抑制和非蛋白酶依赖性激活需要 PYD 和 NAHT 结构域之间的连接。在稳定状态下，Linker1 和 UPA 子结构域之间的相互作用以独立于 DPP9 的方式沉默了包含 DPP9 或不包含 DPP9 的自抑制复合物中 hNLRP1 的激活。ORF45 与 Linker1 的结合取代了 Linker1-UPA 复合物中的 UPA，并诱导 hNLRP1 C 端结构域的释放，用于炎症小体的组装。NLRP1 炎症小体的 ORF45 依赖性激活在灵长类动物中是保守的，但在小鼠 NLRP1b 炎症小体中没有观察到。