DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation.,ACS Chemical Biology

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DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-09-20 , DOI: 10.1021/acschembio.9b00462
Andrew R Griswold _{1,

2} , Daniel P Ball ₃ , Abir Bhattacharjee ₃ , Ashley J Chui ₄ , Sahana D Rao ₄ , Cornelius Y Taabazuing ₃ , Daniel A Bachovchin _{2,

3,

4}

Affiliation

Inflammasomes are multiprotein complexes formed in response to pathogens. NLRP1 and CARD8 are related proteins that form inflammasomes, but the pathogen-associated signal(s) and the molecular mechanisms controlling their activation have not been established. Inhibitors of the serine dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both NLRP1 and CARD8. Interestingly, DPP9 binds directly to NLRP1 and CARD8, and this interaction may contribute to the inhibition of NLRP1. Here, we use activity-based probes, reconstituted inflammasome assays, and mass spectrometry-based proteomics to further investigate the DPP9-CARD8 interaction. We show that the DPP9-CARD8 interaction, unlike the DPP9-NLRP1 interaction, is not disrupted by DPP9 inhibitors or CARD8 mutations that block autoproteolysis. Moreover, wild-type, but not catalytically inactive mutant, DPP9 rescues CARD8-mediated cell death in DPP9 knockout cells. Together, this work reveals that DPP9's catalytic activity and not its binding to CARD8 restrains the CARD8 inflammasome and thus suggests the binding interaction likely serves some other biological purpose.

中文翻译：

DPP9的酶活性而不是其与CARD8的结合抑制了炎性体的激活。

炎性体是响应病原体而形成的多蛋白复合物。NLRP1和CARD8是形成炎症小体的相关蛋白，但尚未确定病原体相关信号和控制其激活的分子机制。丝氨酸二肽基肽酶DPP8和DPP9（DPP8 / 9）的抑制剂激活NLRP1和CARD8。有趣的是，DPP9直接与NLRP1和CARD8结合，这种相互作用可能有助于抑制NLRP1。在这里，我们使用基于活动的探针，重组的炎性体测定法和基于质谱的蛋白质组学来进一步研究DPP9-CARD8的相互作用。我们显示，与DPP9-NLRP1交互作用不同，DPP9-CARD8交互作用不受DPP9抑制剂或阻止自体蛋白水解的CARD8突变的干扰。此外，野生型但非催化失活的突变体 DPP9可以挽救DPP9敲除细胞中CARD8介导的细胞死亡。总之，这项工作揭示了DPP9的催化活性而不是其与CARD8的结合抑制了CARD8炎性小体，因此表明结合相互作用可能具有其他生物学目的。

更新日期：2019-09-21

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