KSHV-encoded ORF45 activates human NLRP1 inflammasome

• DOI: 10.1038/s41590-022-01199-x
• Publication Date: 2022-05-26T16:04:49Z
• Authors: Xing Yang; Jingfan Zhou; Chengrong Liu; Yafei Qu; Weili Wang; Maggie Z. X. Xiao; Fanxiu Zhu; Zhenshan Liu; Qiming Liang
• Keywords: CARD Signaling Adaptor Proteins; Mice; Viral Proteins; 0303 health sciences; 03 medical and health sciences; Inflammasomes; Herpesvirus 8, Human; Animals; Humans; NLR Proteins; 3. Good health

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.