Structural and biochemical mechanisms of NLRP1 inhibition by DPP9
Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND...
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sg-ntu-dr.10356-1613972023-02-28T17:10:44Z Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 Huang, Menghang Zhang, Xiaoxiao Toh, Gee Ann Gong, Qin Wang, Jia Han, Zhifu Wu, Bin Zhong, Franklin Chai, Jijie Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Institute of Structural Biology Science::Biological sciences Inflammasome Domain Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation8,9; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome. Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This research was funded by the National Natural Science Foundation of China (31421001 to J.C.), the Alexander von Humboldt Foundation (a Humboldt professorship to J.C.), Max Planck-Gesellschaft (a Max Planck fellowship to J.C.), the Ministry of Health, Singapore, NMRC grant (MOH-000382-00 to W.B.), the Concern Foundation (F.L.Z), a Nanyang Assistant Professorship (F.L.Z.) and the National Research Foundation fellowship (NRF-NRFF11-2019-0006 to F.L.Z.). 2022-08-30T08:05:54Z 2022-08-30T08:05:54Z 2021 Journal Article Huang, M., Zhang, X., Toh, G. A., Gong, Q., Wang, J., Han, Z., Wu, B., Zhong, F. & Chai, J. (2021). Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature, 592(7856), 773-777. https://dx.doi.org/10.1038/s41586-021-03320-w 0028-0836 https://hdl.handle.net/10356/161397 10.1038/s41586-021-03320-w 33731929 2-s2.0-85102992881 7856 592 773 777 en MOH-000382-00 to W.B. NRF-NRFF11-2019-0006 to F.L.Z. Nature © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
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Science::Biological sciences Inflammasome Domain Huang, Menghang Zhang, Xiaoxiao Toh, Gee Ann Gong, Qin Wang, Jia Han, Zhifu Wu, Bin Zhong, Franklin Chai, Jijie Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
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Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation8,9; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome. |
author2 |
Lee Kong Chian School of Medicine (LKCMedicine) |
author_facet |
Lee Kong Chian School of Medicine (LKCMedicine) Huang, Menghang Zhang, Xiaoxiao Toh, Gee Ann Gong, Qin Wang, Jia Han, Zhifu Wu, Bin Zhong, Franklin Chai, Jijie |
format |
Article |
author |
Huang, Menghang Zhang, Xiaoxiao Toh, Gee Ann Gong, Qin Wang, Jia Han, Zhifu Wu, Bin Zhong, Franklin Chai, Jijie |
author_sort |
Huang, Menghang |
title |
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
title_short |
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
title_full |
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
title_fullStr |
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
title_full_unstemmed |
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9 |
title_sort |
structural and biochemical mechanisms of nlrp1 inhibition by dpp9 |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/161397 |
_version_ |
1759857928976728064 |