IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.
IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.
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DOI：
10.1016/j.cmet.2012.07.007
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发表时间：
2012-08-08
期刊：
影响因子：
29
通讯作者：
Papa FR
中科院分区：
文献类型：
--
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
当展开的蛋白质在内质网（ER）内积累到不受欢迎的高水平时，称为展开的蛋白质反应（UPR）的细胞内信号传导途径过度活化以引起硫糖蛋白交互蛋白（TXNIP）。这种“终端UPR。激活NLRP3炎性体，引起caspase-1裂解和白介素1β（IL-1β）的分泌。 RNase抑制剂抑制TxNIP产生以阻止IL-1β的分泌，在末端UPR中使用IRE1α-TXNIP途径来促进无菌感染和程序性细胞死亡，并且可以针对细胞退化疾病的有效治疗。
When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this “Terminal UPR.” TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing micro-RNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing Caspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β-cell death during ER stress, and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death, and may be targeted to develop effective treatments for cell degenerative diseases.
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影响因子：
56.9
作者：
Papa, FR;Zhang, C;Walter, P
通讯作者：
Walter, P
DOI：
10.1101/sqb.2001.66.499
发表时间：
2001-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
56.9
作者：
Lee, Ann-Hwee;Scapa, Erez F.;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
TXNIP调节人类的外周葡萄糖代谢。
影响因子：
15.8
作者：
Parikh, Hemang;Carlsson, Emma;Chutkow, William A.;Johansson, Lovisa E.;Storgaard, Heidi;Poulsen, Pernille;Saxena, Richa;Ladd, Christine;Schulze, P. Christian;Mazzini, Michael J.;Jensen, Christine Bjorn;Krook, Anna;Bjornholm, Marie;Tornqvist, Hans;Zierath, Juleen R.;Ridderstrale, Martin;Altshuler, David;Lee, Richard T.;Vaag, Allan;Groop, Leif C.;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.