NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes.
NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes.
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DOI：
10.1038/s41420-023-01495-x
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发表时间：
2023-07-28
影响因子：
7
通讯作者：
Yin, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Khambu, Bilon;Cai, Genxiang;Liu, Gang;Bailey, Niani Tiaye;Mercer, Arissa A. A.;Baral, Kamal;Ma, Michelle;Chen, Xiaoyun;Li, Yu;Yin, Xiao-Ming
损伤或应激可诱导细胞内易位和核HMGB 1的释放，HMGB 1是已知参与炎症和其他病理过程的DAMP分子。HMGB 1从刺激的巨噬细胞中的主动释放可以由炎性体介导，炎性体切割Gasdermin D在细胞质膜上形成孔。我们以前已经表明，自噬缺陷肝细胞中HMGB 1的主动释放也依赖于炎性小体，但炎性小体如何被激活尚不清楚。在此，我们报道了在自噬缺陷条件下转录因子NRF 2的持续激活导致Caspase-11表达的转录上调，从而激活Caspase-1炎性体。使用染色质免疫沉淀（CHIP）和基于端粒酶的报告分析，我们表明，NRF 2直接结合到Caspase-11启动子和转录增加Caspase-11的表达。自噬缺陷肝脏中Caspase-11的基因缺失抑制HMGB 1的释放及其病理后果，小管细胞增殖。一致地，在其他类型的信号下可以激活半胱天冬酶-1介导的炎性体的NLRP 3的缺失并不能阻止自噬缺陷肝脏中HMGB 1的释放和小管细胞增殖。令人惊讶的是，虽然GASDEMIN D的裂解发生在自噬缺陷的肝脏中，但其缺失并不阻止HMGB 1的释放，这表明半胱天冬酶-11介导的炎性小体激活也可能参与自噬缺陷肝细胞释放HMGB 1的不同机制。总的来说，这项工作揭示了NRF 2在Caspase-11转录上调和炎性小体激活中的新作用，以通过非Gasdermin D介导的途径促进HMGB的主动释放。
Injury or stress can induce intracellular translocation and release of nuclear HMGB1, a DAMP molecule known to participate in inflammation and other pathological processes. Active release of HMGB1 from stimulated macrophages can be mediated by inflammasomes, which cleave Gasdermin D to form pores on cytoplasmic membranes. We previously had shown that active release of HMGB1 from autophagy deficient hepatocytes also depended on the inflammasome but how the inflammasome was activated was not known. Here we report that persistent activation of transcription factor NRF2 under the autophagy deficient condition led to transcriptional upregulation of Caspase-11 expression, which could then activate the CASPASE-1inflammasome. Using chromatin immunoprecipitation (CHIP) and luciferase-based reporter assays, we show that NRF2 directly binds to the Caspase-11 promoter and transcriptionally increase the expression of Caspase-11. Genetic deletion of Caspase-11 in autophagy-deficient livers represses the release of HMGB1 and its pathological consequence, ductular cell proliferation. Consistently, deletion of NLRP3, which can activate CASPASE-1 mediated inflammasomes under other types of signals, did not prevent HMGB1 release and ductular cell proliferation in autophagy deficient livers. Surprisingly, while cleavage of GASDEMIN D occurred in autophagy-deficient livers its deletion did not prevent the HMGB1 release, suggesting that CASPASE-11-mediated inflammasome activation may also engage in a different mechanism for HMGB1 release by the autophagy deficient hepatocytes. Collectively, this work reveals the novel role of NRF2 in transcriptional upregulation of Caspase-11 and in inflammasome activation to promote active release of HMGB via a non-Gasdermin D mediated avenue.
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DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
3.5
作者：
GORR, SU;DARLING, DS
通讯作者：
DARLING, DS
影响因子：
13.5
作者：
Koehler, Ulrike A.;Kurinna, Svitlana;Werner, Sabine
通讯作者：
Werner, Sabine
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA