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首页> 外文期刊>Cell metabolism >Targeting ABL-IRE1 alpha Signaling Spares ER- Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes
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Targeting ABL-IRE1 alpha Signaling Spares ER- Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes

机译:靶向ABL-IRE1α信号备件逆应胰腺β细胞逆转自身免疫糖尿病

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摘要

In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1 alpha-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1 alpha's enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1 alpha's RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1 alpha interaction, blunts IRE1 alpha RNase hyperactivity, reduces pancreatic beta cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1 alpha's RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing beta cells and preserving their physiological function. Our data support a model wherein ER-stressed beta cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1 alpha axis as a drug target for the treatment of an autoimmune disease.
机译:在经历未缓解内质网(ER)应激的细胞中,内质网跨膜激酶/核糖核酸酶(RNase)-IRE1α内核降解内质网定位的mRNA以促进细胞凋亡。在这里,我们发现ABL家族的酪氨酸激酶可变地增强IRE1α的酶活性,从而增强内质网应激诱导的细胞凋亡。在内质网应激期间,胞浆ABL激酶定位于内质网膜,在那里它们结合、支撑并过度激活IRE1α的RNase。在非肥胖糖尿病(NOD)小鼠模型中,伊马替尼是一种抗癌酪氨酸激酶抑制剂,可拮抗ABL-IRE1α相互作用,钝化IRE1αRNA酶的活性,减少胰腺β细胞凋亡,逆转1型糖尿病(T1D)。一种可变构减弱IRE1α的核糖核酸酶-KIRA8-的单选择性激酶抑制剂也能通过保护β细胞和维持其生理功能有效逆转NOD小鼠中已建立的糖尿病。我们的数据支持这样一个模型,即内质网应激的β细胞在T1D发病过程中导致自身死亡,并暗示ABL-IRE1α轴是治疗自身免疫性疾病的药物靶点。

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