Journal
NATURE IMMUNOLOGY
Volume 23, Issue 6, Pages 916-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-022-01199-x
Keywords
-
Categories
Funding
- National Key Research and Development Project of China [2018YFA0900802]
- Shanghai Science and Technology Commission [22ZR1454500]
- Shanghai Frontiers Science Center of Cellular Homeostasis and Human Disease
- Shanghai Municipal Science and Technology Major Project [ZD2021CY001]
- Innovative Research Team of High-level Local Universities in Shanghai
- Shanghai Municipal Health Commission [201940179]
Ask authors/readers for more resources
The ORF45 protein from Kaposi's sarcoma-associated herpesvirus activates NLRP1 by binding to its Linker1 region using a mechanism distinct from the previously described DPP9-dependent mechanism of NLRP1 activation.
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. Liang and colleagues show that the ORF45 protein from the Kaposi's sarcoma-associated herpesvirus activates NLRP1 by binding to its Linker1 region through a mechanism distinct from the previously described, host protease DPP9-dependent mechanism of NLRP1 activation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available