Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response
Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response
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DOI：
10.1016/j.cell.2005.11.040
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发表时间：
2006-02-10
期刊：
影响因子：
64.5
通讯作者：
Kaufman, RJ
中科院分区：
文献类型：
--
作者：
Zhang, KZ;Shen, XH;Kaufman, RJ
内质网（ER）膜锚定转录因子的调节性膜内蛋白水解（RIP）是维持固醇稳态和介导未折叠蛋白反应（UPR）的重要机制。在这里，我们确定CREBH作为RIP调节的肝脏特异性转录因子，其在ER应激时被切割，并需要激活急性期反应（APR）基因的表达。促炎细胞因子增加ER膜锚定的CREBH的表达。响应于ER应激，CREBH被位点1和位点2蛋白酶切割以释放氨基末端片段，该氨基末端片段转运至细胞核以激活编码血清淀粉样蛋白P组分（SAP）和C反应蛋白（CRP）的基因的转录。促炎细胞因子和脂多糖激活UPR并诱导体内肝脏中CREBH的裂解。总之，我们的研究描绘了ER定位的转录因子CREBH激活的分子机制，并揭示了ER应激引发急性炎症反应的前所未有的联系。
Regulated intramembrane proteolysis (RIP) of endoplasmic reticulum (ER) membrane-anchored transcription factors is known to maintain sterol homeostasis and to mediate the unfolded protein response (UPR). Here, we identified CREBH as a RIP-regulated liver-specific transcription factor that is cleaved upon ER stress and required to activate expression of acute phase response (APR) genes. Proinflammatory cytokines increase expression of ER membrane-anchored CREBH. In response to ER stress, CREBH is cleaved by site-1 and site-2 proteases to liberate an amino-terminal fragment that transits to the nucleus to activate transcription of the genes encoding serum amyloid P-component (SAP) and C-reactive protein (CRP). Proinflammatory cytokines and lipopolysaccharide activate the UPR and induce cleavage of CREBH in the liver in vivo. Together, our studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response.