Druggable sensors of the unfolded protein response

被引:166
作者
Maly, Dustin J. [1 ]
Papa, Feroz R. [2 ,3 ,4 ,5 ]
机构
[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Lung Biol Ctr, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; ER STRESS; QUALITY-CONTROL; CELL-DEATH; MESSENGER-RNA; IRE1; REVEALS; IRE1-ALPHA; ACTIVATION; INDUCTION; XBP1;
D O I
10.1038/nchembio.1664
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfolded protein response (UPR). When activated, the UPR induces transcriptional and translational programs that restore ER homeostasis. However, under high-level or chronic ER stress, these adaptive changes ultimately become overshadowed by alternative 'terminal UPR' signals that actively commit cells to degeneration, culminating in programmed cell death. Chronic ER stress and maladaptive UPR signaling are implicated in the etiology and pathogenesis of myriad human diseases. Naturally, this has generated widespread interest in targeting key nodal components of the UPR as therapeutic strategies. Here we summarize the state of this field with emphasis placed on two of the master UPR regulators, PERK and IRE1 alpha, which are both capable of being drugged with small molecules.
引用
收藏
页码:892 / 901
页数:10
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