小柯机器人

美国哈佛医学院Hao Wu、纪念斯隆-凯特琳癌症中心Daniel A. Bachovchin等研究人员合作发现，DPP9通过隔离NLRP1的C末端来抑制炎症小体激活。2021年3月17日，《自然》杂志在线发表了这项成果。

据研究人员介绍，NLRP1（nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1）是炎症小体的传感器，并介导caspase-1的激活来诱导细胞因子成熟和发烧。NLRP1的功能获得性突变会引起严重的皮肤炎性疾病。NLRP1包含一个功能齐全的结构域，可自动蛋白水解成非共价结合的亚结构域，并且NLRP1的阻抑性N末端片段的蛋白酶体降解释放了其炎症性C末端片段（NLRP1 CT）。胞质二肽基肽酶8和9（以下称为DPP8/DPP9）均与NLRP1相互作用，DPP8/DPP9的小分子抑制剂通过目前尚不清楚的机制激活NLRP1。

研究人员报道了单独的人类NLRP1-DPP9复合物以及与DPP8/DPP9抑制剂Val-boroPro（VbP）结合的冷冻电镜结构。该结构揭示了包含DPP9、全长NLRP1和NLRPT CT的三元复合物。NLRP1 CT与DPP9的结合需要全长NLRP1，这表明NLRP1激活受NLRP1 CT与全长NLRP1之比的调节。异位表达NLRP1 CT激活的炎症小体始终可通过共表达自水解缺陷型全长NLRP1来拯救。NLRP1 CT的N末端插入DPP9活性位点，而VbP破坏了这种相互作用。因此，VbP减弱了NLRP1-DPP9的相互作用，并加速了N末端片段的降解，进而诱导炎症小体的活化。

总体而言，这些数据表明，DPP9可阻止低水平的NLRP1 CT，因此可作为激活NLRP1炎症小体的检查点。 

附：英文原文

Title: DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation

Author: L. Robert Hollingsworth, Humayun Sharif, Andrew R. Griswold, Pietro Fontana, Julian Mintseris, Kevin B. Dagbay, Joao A. Paulo, Steven P. Gygi, Daniel A. Bachovchin, Hao Wu

Issue&Volume: 2021-03-17

Abstract: 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 pyroptosis1,2,3,4. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin4,5,6. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains7,8,9, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)10,11. 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 unclear10,12,13,14. 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 fragment10 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.

DOI: 10.1038/s41586-021-03350-4

Source: https://www.nature.com/articles/s41586-021-03350-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html