Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation.
Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation.
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DOI：
10.1016/j.celrep.2022.111965
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发表时间：
2023-01
期刊：
影响因子：
8.8
通讯作者：
Elizabeth L. Orth-He;Hsin-Che Huang;Sahana D. Rao;Qinghui Wang;Qifeng Chen;Claire M. O’Mara;Ashley J. Chui;Michelle Saoi;A. R. Griswold;A. Bhattacharjee;D. Ball;J. Cross;D. Bachovchin
中科院分区：
文献类型：
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作者：
Elizabeth L. Orth-He;Hsin-Che Huang;Sahana D. Rao;Qinghui Wang;Qifeng Chen;Claire M. O’Mara;Ashley J. Chui;Michelle Saoi;A. R. Griswold;A. Bhattacharjee;D. Ball;J. Cross;D. Bachovchin
NLRP 1和CARD 8是相关的模式识别受体（PRR），其检测细胞内危险信号并形成炎性小体。两者都经历自身蛋白水解，产生N-末端（NT）和C-末端（CT）片段。蛋白酶体介导的NT降解使CT从自抑制中释放，但触发NT降解的刺激尚未完全阐明。在这里，我们表明，几种不同的代理商，干扰蛋白质折叠，包括氨肽酶抑制剂，伴侣抑制剂，和诱导剂的展开蛋白质的反应，加速NT降解。然而，这些试剂单独不触发炎性小体形成，因为释放的CT片段被丝氨酸二肽酶DPP 9物理隔离。我们表明，DPP 9结合配体也必须存在，以破坏这些复合物，并允许CT片段寡聚成炎性小体。总体而言，这些结果表明NLRP 1和CARD 8检测到诱导蛋白质折叠应激和DPP 9配体积累的特定扰动。
NLRP1 and CARD8 are related pattern-recognition receptors (PRRs) that detect intracellular danger signals and form inflammasomes. Both undergo autoproteolysis, generating N-terminal (NT) and C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the stimuli that trigger NT degradation have not been fully elucidated. Here, we show that several distinct agents that interfere with protein folding, including aminopeptidase inhibitors, chaperone inhibitors, and inducers of the unfolded protein response, accelerate NT degradation. However, these agents alone do not trigger inflammasome formation because the released CT fragments are physically sequestered by the serine dipeptidase DPP9. We show that DPP9-binding ligands must also be present to disrupt these complexes and allow the CT fragments to oligomerize into inflammasomes. Overall, these results indicate that NLRP1 and CARD8 detect a specific perturbation that induces both protein folding stress and DPP9 ligand accumulation.