The NLRP1 and CARD8 inflammasomes detect reductive stress.
The NLRP1 and CARD8 inflammasomes detect reductive stress.
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NLRP1和CARD8炎症体检测还原应力。
DOI：
10.1016/j.celrep.2022.111966
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发表时间：
2023-01-31
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
激活相关核苷酸结合结构域富含亮氨酸的重复pyrin结构域1 （NLRP1）和caspase激活和募集结构域8 （CARD8）炎症小体的危险信号尚未完全确定。我们最近报道了TRX1的氧化形式与NLRP1结合并抑制炎性体的激活。这些发现表明，细胞内还原性应激是NLRP1炎症小体激活的危险信号，它可以降低氧化TRX1，从而消除NLRP1-TRX1的相互作用。然而，没有已知的诱导还原性应激的药物来测试这一前提。在这里，我们鉴定和表征了几种自由基捕获抗氧化剂，包括JSH-23，诱导还原性应激。我们发现，这些化合物加速了蛋白酶体介导的NLRP1和CARD8的抑制性n端片段的降解，将炎症小体形成的c端片段从自抑制中释放出来。总的来说，这项工作验证了诱导还原性应激的化学探针，并将还原性应激作为NLRP1和CARD8炎症小体都能感知的危险信号。Wang等人报道了诱导细胞内还原性应激的小分子。这些分子加速NLRP1和CARD8 n端抑制片段的降解，从而增强炎症小体的激活。这些结果强烈表明NLRP1和CARD8检测到还原应力。
The danger signals that activate the related nucleotide-binding domain leucine-rich repeat pyrin domain-containing 1 (NLRP1) and caspase activation and recruitment domain-containing 8 (CARD8) inflammasomes have not been fully established. We recently reported that the oxidized form of TRX1 binds to NLRP1 and represses inflammasome activation. These findings suggested that intracellular reductive stress, which would reduce oxidized TRX1 and thereby abrogate the NLRP1-TRX1 interaction, is an NLRP1 inflammasome-activating danger signal. However, no agents that induce reductive stress were known to test this premise. Here, we identify and characterize several radical-trapping antioxidants, including JSH-23, that induce reductive stress. We show that these compounds accelerate the proteasome-mediated degradation of the repressive N-terminal fragments of both NLRP1 and CARD8, releasing the inflammasome-forming C-terminal fragments from autoinhibition. Overall, this work validates chemical probes that induce reductive stress and establishes reductive stress as a danger signal sensed by both the NLRP1 and CARD8 inflammasomes. Wang et al. report small molecules that induce intracellular reductive stress. These molecules accelerate the degradation of the NLRP1 and CARD8 N-terminal repressive fragments, thereby potentiating inflammasome activation. These results strongly indicate that NLRP1 and CARD8 detect reductive stress.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
14.8
作者：
Conlon M;Poltorack CD;Forcina GC;Armenta DA;Mallais M;Perez MA;Wells A;Kahanu A;Magtanong L;Watts JL;Pratt DA;Dixon SJ
通讯作者：
Dixon SJ
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.8
作者：
Hollingsworth LR;Sharif H;Griswold AR;Fontana P;Mintseris J;Dagbay KB;Paulo JA;Gygi SP;Bachovchin DA;Wu H
通讯作者：
Wu H
影响因子：
4.8
作者：
Geiss-Friedlander, Ruth;Parmentier, Nicolas;Melchior, Frauke
通讯作者：
Melchior, Frauke