Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.
Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.
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DOI：
10.1016/j.cell.2014.07.002
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发表时间：
2014-07-31
期刊：
影响因子：
64.5
通讯作者：
Papa FR
中科院分区：
文献类型：
--
作者：
Ghosh R;Wang L;Wang ES;Perera BG;Igbaria A;Morita S;Prado K;Thamsen M;Caswell D;Macias H;Weiberth KF;Gliedt MJ;Alavi MV;Hari SB;Mitra AK;Bhhatarai B;Schürer SC;Snapp EL;Gould DB;German MS;Backes BJ;Maly DJ;Oakes SA;Papa FR
内质网（ER）应激水平不同，内质网跨膜多结构域蛋白IRE1α可促进适应或细胞凋亡。未折叠的ER蛋白导致IRE1α管腔结构域同源寡聚，诱导反式自磷酸化，进而驱动其胞浆激酶/核糖核酸内切酶（RNase）结构域同源寡聚，从而激活适应性XBP1转录因子的mRNA剪接。然而，在高/慢性内质网应激下，IRE1α超过寡聚化阈值，将RNase底物库扩展到许多内质网定位的mrna，导致细胞凋亡。为了调节这些影响，我们开发了atp竞争性IRE1α激酶抑制RNase衰减剂- kiras -通过破坏低聚物来变构抑制IRE1α的RNase。其中一个优化的KIRA KIRA6在体内抑制IRE1α，促进内质网应激下的细胞存活。在玻璃体内，KIRA6在内质网应激性视网膜变性大鼠模型中保持了光感受器功能的活力。在系统上，KIRA6保存胰腺β细胞，增加胰岛素，降低秋田糖尿病小鼠的高血糖。因此，IRE1α强有力地控制着细胞的命运，但它本身也可以用小分子来控制，以减少细胞的退化。
Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multi-domain protein IRE1α promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1α lumenal domain homo-oligomerization, inducing trans auto-phosphorylation that further drives homo-oligomerization of its cytosolic kinase/ endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1α Kinase Inhibiting RNase Attenuators—KIRAs—that allosterically inhibit IRE1α’s RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1α in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic β-cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1α powerfully controls cell fate, but can itself be controlled with small molecules to reduce cell degeneration.
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影响因子：
29
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
通讯作者：
Papa FR
影响因子：
64.8
作者：
Reimold, AM;Iwakoshi, NN;Glimcher, LH
通讯作者：
Glimcher, LH
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
DOI：
10.3791/255
发表时间：
2007-01-01
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Szot, Gregory L;Koudria, Pavel;Bluestone, Jeffrey A
通讯作者：
Bluestone, Jeffrey A
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D