PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling.
PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling.
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DOI：
10.1002/ibd.22878
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发表时间：
2012-09
影响因子：
4.9
通讯作者：
Kaufman, Randal J.
中科院分区：
文献类型：
--
作者：
Siyan, Stewart;Song, Benbo;Kaufman, Randal J.
dsrna激活的蛋白激酶（PKR）磷酸化真核翻译起始因子2 （eIF2α）的α亚基，eIF2α是哺乳动物蛋白质合成的全局调节因子。此外，PKR激活包括STAT3和AKT在内的多种信号转导通路。PKR被炎症肠内诱导的许多炎症刺激激活。在这项研究中，我们打算确定PKR在实验性结肠炎小鼠结肠上皮细胞中的作用。年龄和性别匹配的PKR+/+，+/ -和PKR - / -同窝小鼠用野生型骨髓细胞重建，并进行葡聚糖硫酸钠（DSS）诱导的结肠炎。与PKR+/+、+/−同窝的小鼠相比，PKR−/−小鼠在DSS结肠炎时表现出更严重的临床和组织学表现。在DSS结肠炎的反应中，PKR - / -小鼠的结肠上皮细胞表现出未折叠蛋白反应（UPR）信号的激活受损，包括eIF2α磷酸化、内质网（ER）伴侣反应、ER相关降解（ERAD）成分以及抗氧化应激反应。此外，在DSS结肠炎的PKR - / -小鼠的结肠上皮细胞中，具有保护上皮细胞死亡和结肠炎症的STAT3和AKT的磷酸化也被破坏。这些数据表明，PKR是结肠上皮细胞炎症反应信号的生理相关换能器。PKR可能通过eif2 α-介导的UPR激活，以及STAT3和AKT通路的激活，促进肠上皮细胞（IECs）的稳态和存活。在缺乏PKR的情况下，IECs的存活和增殖受到损害，从而加剧了肠道炎症。
The dsRNA-activated protein kinase (PKR) phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), a global regulator of protein synthesis in mammals. In addition, PKR activates several signal transduction pathways including STAT3 and AKT. PKR is activated by a number of inflammatory stimuli that are induced in the inflamed intestine. In this study we intended to determine the role of PKR in colonic epithelial cells during experimental colitis in mice. Age- and sex-matched PKR+/+,+/− and PKR−/− littermate mice were reconstituted with wildtype bone marrow cells and subjected to dextran sodium sulfate (DSS)-induced colitis. PKR−/− mice displayed more severe clinical and histological manifestations upon DSS colitis compared with their PKR+/+,+/− litter-mates. In response to DSS colitis, the colonic epithelial cells of PKR−/− mice exhibited impaired activation of the unfolded protein response (UPR) signaling, including eIF2α phosphorylation, endoplasmic reticulum (ER) chaperone response, and ER-associated degradation (ERAD) components, as well as antioxidative stress response. In addition, the phosphorylation of STAT3 and AKT, which are protective against epithelial cell death and colonic inflammation, was also impaired in the colonic epithelial cells of PKR−/− mice upon DSS colitis. These data demonstrate that PKR is a physiologically relevant transducer of inflammatory response signaling in colonic epithelial cells. PKR may promote the homeostasis and survival of intestinal epithelial cells (IECs) through eIF2α-mediated UPR activation, as well as the activation of STAT3 and AKT pathways. In the absence of PKR, the survival and proliferation of IECs was impaired, thus exacerbating intestinal inflammation.
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DOI：
10.1073/pnas.0813036106
发表时间：
2009-03-03
影响因子：
11.1
作者：
Brandl, Katharina;Rutschmann, Sophie;Beutler, Bruce
通讯作者：
Beutler, Bruce
DOI：
10.1084/jem.20082683
发表时间：
2009-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pickert G;Neufert C;Leppkes M;Zheng Y;Wittkopf N;Warntjen M;Lehr HA;Hirth S;Weigmann B;Wirtz S;Ouyang W;Neurath MF;Becker C
通讯作者：
Becker C
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA
影响因子：
4.8
作者：
Baltzis, D;Lit, SY;Koromilas, AE
通讯作者：
Koromilas, AE
影响因子：
29.4
作者：
Otsuka M;Kang YJ;Ren J;Jiang H;Wang Y;Omata M;Han J
通讯作者：
Han J