DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
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DOI：
10.1038/s41586-021-03350-4
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发表时间：
2021-04
期刊：
影响因子：
64.8
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Hollingsworth LR;Sharif H;Griswold AR;Fontana P;Mintseris J;Dagbay KB;Paulo JA;Gygi SP;Bachovchin DA;Wu H
核巧酸结合域和富含亮氨酸重复的化rin-domain containing protein 1（NLRP 1）是一种炎性感受器，其介导半脱天冬酶-1活化W诱导细胞因子成熟和细胞质焦亡。NLRP 1的功能获得性突变导致严重的皮肤炎性疾病。NLRP 1含有一个发现功能的结构域，该结构域自身蛋白水解成非共价结合的亚结构域，并且NLRP 1的抑制性N-末端片段的蛋白酶体降解释放其炎性C-末端片段（NLRP 1 CT）。胞质二肽基肽酶8和9（下文中，DPP 8/DPP 9）都与NLRP 1相互作用，并且DPP 8/DPP 9的小分子抑制剂通过目前尚不清楚的机制激活NLRP 1。在这里，我们报告冷冻电子显微镜结构的人NLRP 1-DPP 9复合物单独和Val-boroPro（VbP），DPP 8/DPP 9的抑制剂。结构揭示了包含DPP 9、全长NLRP 1和NLRPT CT的三元复合物。NLRP 1 CT与DPP 9的结合需要全长NLRP 1，这表明NLRP 1激活受NLRP 1 CT与全长NLRP 1的比率调节。通过异位表达NLRP 1 CT激活炎性小体始终通过共表达自身蛋白水解缺陷型全长NLRP 1来拯救。NLRP 1 CT的N末端插入DPP 9活性位点，VbP破坏这种相互作用。因此，VbP减弱NLRP 1-DPP 9相互作用并加速N-末端片段的降解以诱导炎性小体活化。总体而言，这些数据表明，DPP 9淬灭低水平的NLRP 1 CT，因此充当NLRP 1炎性体激活的检查点。
Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis, , –. Gain-of-function mutations ofNLRP1cause severe inflammatory diseases of the skin, –. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains, –, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT),. Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear,, –. Here we report cryo-electron microscopy structures of the human NLRP1–DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1–DPP9 interaction and accelerates degradation of the N-terminal fragment to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome.
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