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The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2024-07-10 , DOI: 10.1016/j.chembiol.2024.06.004 Lydia P Tsamouri 1 , Jeffrey C Hsiao 1 , Qinghui Wang 2 , Michael B Geeson 2 , Hsin-Che Huang 3 , Deepika R Nambiar 3 , Mengyang Zou 4 , Daniel P Ball 2 , Ashley J Chui 3 , Daniel A Bachovchin 5
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2024-07-10 , DOI: 10.1016/j.chembiol.2024.06.004 Lydia P Tsamouri 1 , Jeffrey C Hsiao 1 , Qinghui Wang 2 , Michael B Geeson 2 , Hsin-Che Huang 3 , Deepika R Nambiar 3 , Mengyang Zou 4 , Daniel P Ball 2 , Ashley J Chui 3 , Daniel A Bachovchin 5
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Mounting evidence indicates that proteotoxic stress is a primary activator of the CARD8 inflammasome, but the complete array of signals that control this inflammasome have not yet been established. Notably, we recently discovered that several hydrophobic radical-trapping antioxidants (RTAs), including JSH-23, potentiate CARD8 inflammasome activation through an unknown mechanism. Here, we report that these RTAs directly alkylate several cysteine residues in the N-terminal disordered region of CARD8. These hydrophobic modifications destabilize the repressive CARD8 N-terminal fragment and accelerate its proteasome-mediated degradation, thereby releasing the inflammatory CARD8 C-terminal fragment from autoinhibition. Consistently, we also found that unrelated (non-RTA) hydrophobic electrophiles as well as genetic mutation of the CARD8 cysteine residues to isoleucines similarly potentiate inflammasome activation. Overall, our results not only provide further evidence that protein folding stress is a key CARD8 inflammasome-activating signal, but also indicate that the N-terminal cysteines can play key roles in tuning the response to this stress.
中文翻译：
CARD8 N 末端的疏水性调节炎症小体的激活
越来越多的证据表明，蛋白毒性应激是 CARD8 炎症小体的主要激活剂，但控制该炎症小体的完整信号序列尚未确定。值得注意的是，我们最近发现几种疏水性自由基捕获抗氧化剂 (RTA)，包括 JSH-23，通过未知机制增强 CARD8 炎性体激活。在这里，我们报告这些 RTA 直接烷基化 CARD8 N 末端无序区域中的几个半胱氨酸残基。这些疏水性修饰破坏了抑制性 CARD8 N 端片段的稳定性，并加速其蛋白酶体介导的降解，从而释放炎症性 CARD8 C 端片段的自身抑制。一致地，我们还发现不相关的（非 RTA）疏水性亲电子试剂以及 CARD8 半胱氨酸残基向异亮氨酸的基因突变同样会增强炎症小体的激活。总的来说，我们的结果不仅提供了进一步的证据表明蛋白质折叠应激是关键的 CARD8 炎症小体激活信号，而且还表明 N 末端半胱氨酸在调节对这种应激的反应中可以发挥关键作用。
更新日期：2024-07-10
中文翻译：
CARD8 N 末端的疏水性调节炎症小体的激活
越来越多的证据表明，蛋白毒性应激是 CARD8 炎症小体的主要激活剂，但控制该炎症小体的完整信号序列尚未确定。值得注意的是，我们最近发现几种疏水性自由基捕获抗氧化剂 (RTA)，包括 JSH-23，通过未知机制增强 CARD8 炎性体激活。在这里，我们报告这些 RTA 直接烷基化 CARD8 N 末端无序区域中的几个半胱氨酸残基。这些疏水性修饰破坏了抑制性 CARD8 N 端片段的稳定性，并加速其蛋白酶体介导的降解，从而释放炎症性 CARD8 C 端片段的自身抑制。一致地，我们还发现不相关的（非 RTA）疏水性亲电子试剂以及 CARD8 半胱氨酸残基向异亮氨酸的基因突变同样会增强炎症小体的激活。总的来说，我们的结果不仅提供了进一步的证据表明蛋白质折叠应激是关键的 CARD8 炎症小体激活信号，而且还表明 N 末端半胱氨酸在调节对这种应激的反应中可以发挥关键作用。
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