Activation of the CARD8 Inflammasome Requires a Disordered Region.
Activation of the CARD8 Inflammasome Requires a Disordered Region.
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Card8炎性体的激活需要一个无序区域。
DOI：
10.1016/j.celrep.2020.108264
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发表时间：
2020-10-13
期刊：
影响因子：
8.8
通讯作者：
Bachovchin DA
中科院分区：
文献类型：
--
作者：
Chui AJ;Griswold AR;Taabazuing CY;Orth EL;Gai K;Rao SD;Ball DP;Hsiao JC;Bachovchin DA
几种胞质模式识别受体（PRR）形成多蛋白复合物，称为典型炎性小体，以响应细胞内的危险信号。典型炎性小体募集并激活半胱天冬酶-1（CASP 1），半胱天冬酶-1又切割并激活炎性细胞因子和gasdermin D（GSDMD），诱导细胞死亡。二肽基肽酶DPP 8和DPP 9（DPP 8/9）的抑制剂激活人NLRP 1和CARD 8炎性体。NLRP 1和CARD 8具有不同的N-末端区域，但具有相似的C-末端区域，其经历蛋白质自水解以产生两个非共价结合的片段。在这里，我们表明，DPP 8/9抑制激活蛋白酶体降解途径，目标是破坏无序和错误折叠的蛋白质。CARD 8的N末端包含约160个氨基酸的无序区域，该区域被该降解途径识别和破坏，从而释放其C末端片段以激活CASP 1并诱导细胞凋亡。因此，CARD 8作为一个警报信号的降解途径的激活无序和错误折叠的蛋白质。炎性小体是一种多蛋白复合物，可以检测细胞内的危险信号并刺激强大的免疫反应。DPP 8/9抑制剂通过未知机制激活CARD 8炎性体。在这里，Chui等人表明DPP 8/9抑制剂诱导许多无序和错误折叠的蛋白质的降解。CARD 8具有N-末端无序区域，其在DPP 8/9抑制后降解，触发炎性小体形成。
Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8’s N terminus contains a disordered region of ~160 amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins. Inflammasomes are multiprotein complexes that detect intracellular danger signals and stimulate powerful immune responses. DPP8/9 inhibitors activate the CARD8 inflammasome through an unknown mechanism. Here, Chui et al. show that DPP8/9 inhibitors induce the degradation of many disordered and misfolded proteins. CARD8 has an N-terminal disordered region that is degraded upon DPP8/9 inhibition, triggering inflammasome formation.
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