Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.
Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.
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DOI：
10.1038/ncb1996
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发表时间：
2009-12
影响因子：
21.3
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Woo, Connie W.;Cui, Dongying;Arellano, Jerry;Dorweiler, Bernhard;Harding, Heather;Fitzgerald, Katherine A.;Ron, David;Tabas, Ira
内质网(ER)未折叠蛋白反应(UPR)恢复了对ER的平衡，但UPR效应元件CHOP(GADD153)的长期表达具有细胞毒性。我们发现，通过TRIF依赖的途径，Toll样受体(TLR)3或4的预先参与抑制了内质网应激诱导的CHOP表达。TLR的参与不能抑制CHOP上游的PERK或eIF-2α的磷酸化，但磷酸化的eIF-2α不能促进CHOP激活剂ATF4的翻译。在全身性内质网应激小鼠中，TLR4配体小剂量脂多糖可抑制小鼠脾巨噬细胞、肾小管细胞和肝细胞的CHOP表达和细胞凋亡，从而预防肾功能障碍和肝骨病。这种内毒素的保护作用在TRIF−/−小鼠和CHOP基因恢复表达的野生型小鼠中都没有发生。因此，来自TLRs的TRIF介导的信号选择性地减弱ATF4及其下游靶基因CHOP的翻译激活。我们推测，这种机制的进化是为了促进TLR表达细胞的存活，这些细胞在宿主对入侵病原体的反应过程中经历了长期的生理性内质网应激。
The endoplasmic reticulum (ER) Unfolded Protein Response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that ER stress-induced CHOP expression was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2α, which are upstream of CHOP, but phospho-eIF-2α failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pre-treatment with low-dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells, and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif−/− mice nor in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiologic ER stress in the course of the host response to invading pathogens.
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影响因子：
11.8
作者：
Rutkowski, D. Thomas;Wu, Jun;Back, Sung-Hoon;Callaghan, Michael U.;Ferris, Sean P.;Iqbal, Jahangir;Clark, Robert;Miao, Hongzhi;Hassler, Justin R.;Fornek, Jamie;Katze, Michael G.;Hussain, M. Mahmood;Song, Benbo;Swathirajan, Jayanth;Wang, Junying;Yau, Grace D. -Y.;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
4.8
作者：
Li, YK;Ge, MT;Tabas, I
通讯作者：
Tabas, I
影响因子：
21.3
作者：
Feng, B;Yao, PM;Tabas, I
通讯作者：
Tabas, I
影响因子：
15.9
作者：
Song, Benbo;Scheuner, Donalyn;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
DOI：
10.1111/j.1432-1033.1982.tb07022.x
发表时间：
1982-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DUKSIN, D;SEIBERG, M;MAHONEY, WC
通讯作者：
MAHONEY, WC