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NLRP1 抑制物 DPP9 的结构和生化机制。

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9.

机构信息

Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China.

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

出版信息

Nature. 2021 Apr;592(7856):773-777. doi: 10.1038/s41586-021-03320-w. Epub 2021 Mar 17.

DOI:10.1038/s41586-021-03320-w
PMID:33731929
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8081665/
Abstract

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). In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation; 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.

摘要

核苷酸结合域和富含亮氨酸重复序列受体（NLRs）通过形成炎性小体来介导先天免疫。NLR 蛋白 NLRP1 的激活需要其功能寻找结构域（FIIND）内的自身切割。在静息细胞中，二肽基肽酶 DPP8 和 DPP9 与 NLRP1 的 FIIND 相互作用，抑制自发性 NLRP1 激活；然而，这种情况发生的机制仍不清楚。在这里，我们提供了结构和生化证据，表明全长大鼠 NLRP1（rNLRP1）和大鼠 DPP9（rDPP9）形成 2:1 复合物，其中包含一个自动抑制的 rNLRP1 分子和一个活性的 rNLRP1 的 UPA-CARD 片段。ZU5 结构域不仅是 rNLRP1 自动抑制所必需的，也是 2:1 复合物组装所必需的。该复合物的形成阻止了 UPA 介导的 UPA-CARD 片段的高阶寡聚化，并增强了 ZU5 介导的 NLRP1 自动抑制。基于结构的生化和功能测定表明，DPP9 抑制人细胞中的 NLRP1 需要 NLRP1 结合和酶活性。总之，我们的数据揭示了 DPP9 介导的 NLRP1 抑制的机制，并阐明了 NLRP1 炎性小体的激活机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/239fe397c05f/41586_2021_3320_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/239fe397c05f/41586_2021_3320_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/ec4e50b8fb63/41586_2021_3320_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/6b1df9f10953/41586_2021_3320_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/426c6a502121/41586_2021_3320_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/b3bf89c18074/41586_2021_3320_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/49f7cc74139b/41586_2021_3320_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/10889a8fface/41586_2021_3320_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/320fb6a48ac3/41586_2021_3320_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/cac4c3dc24b2/41586_2021_3320_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/906a973e0d3d/41586_2021_3320_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/6e988e84c172/41586_2021_3320_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/470b3344e647/41586_2021_3320_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8081665/239fe397c05f/41586_2021_3320_Fig12_ESM.jpg

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