RACK1在胰島β細胞中內(nèi)質(zhì)網(wǎng)應(yīng)激IRE1信號通路的負反饋調(diào)控中發(fā)揮關(guān)鍵作用
1月27日,，《科學(xué)·信號轉(zhuǎn)導(dǎo)》（Science Signaling）雜志發(fā)表了中國科學(xué)院上海生命科學(xué)研究院營養(yǎng)科學(xué)研究所劉勇研究組的最新研究成果，揭示了腳手架（Scaffold）蛋白RACK1以分子開關(guān)的方式,，在胰島β細胞中內(nèi)質(zhì)網(wǎng)應(yīng)激（ER stress）信號通路的動態(tài)調(diào)控中發(fā)揮關(guān)鍵作用,。
內(nèi)質(zhì)網(wǎng)是細胞內(nèi)蛋白質(zhì)合成折疊、修飾加工與質(zhì)量監(jiān)控的重要場所,，其穩(wěn)態(tài)平衡對于維持正常的細胞功能至關(guān)重要,。當細胞的內(nèi)質(zhì)網(wǎng)難以承擔錯誤折疊蛋白的負荷時則引發(fā)內(nèi)質(zhì)網(wǎng)應(yīng)激，激活未折疊蛋白響應(yīng)（UPR,，Unfolded Protein Response）信號通路,，以此增強內(nèi)質(zhì)網(wǎng)的蛋白加工處理能力。其中一條關(guān)鍵的UPR信號通路由內(nèi)質(zhì)網(wǎng)上的跨膜蛋白IRE1α（Inositol Requiring Enzyme 1α）介導(dǎo),。IRE1α集蛋白激酶與核糖核酸內(nèi)切酶功能于一體,，可以通過自身磷酸化被激活，在內(nèi)質(zhì)網(wǎng)應(yīng)激狀況下參與細胞生死命運的決定，所以對細胞功能的維持具有舉足輕重的作用,。此外,，內(nèi)質(zhì)網(wǎng)應(yīng)激也是關(guān)聯(lián)肥胖、胰島素抵抗和2型糖尿病的重要病理機制之一,；而在專職分泌的胰島β細胞中,，IRE1α信號通路參與調(diào)控胰島素生物合成的過程,。
為了探討IRE1α信號通路的分子調(diào)節(jié)機制及其在胰島β細胞中的功能,，劉勇組博士研究生邱義福等通過一系列信號機制的研究發(fā)現(xiàn),，在胰島β細胞系INS-1和原代培養(yǎng)的胰島中,，葡萄糖刺激或內(nèi)質(zhì)網(wǎng)應(yīng)激能夠誘導(dǎo)RACK1與IRE1α的相互作用,。而RACK1與蛋白磷酸酶PP2A可以組成性地結(jié)合,，并在高葡萄糖的刺激下形成RACK1,、PP2A 和IRE1α的三元復(fù)合物,，由此使IRE1α去磷酸化來控制其激活水平,。與此相反,，在長期高葡萄糖刺激或內(nèi)質(zhì)網(wǎng)應(yīng)激條件下，PP2A與RACK1發(fā)生解離,，使得與RACK1結(jié)合的IRE1α磷酸化水平維持不變,，同時還伴隨著胰島素mRNA水平的下降。這表明在應(yīng)對不同程度的細胞應(yīng)激狀況下,，RACK1對IRE1α信號通路的活性發(fā)揮不同的調(diào)節(jié)效應(yīng),。另一方面，在db/db糖尿病小鼠的胰島中,，RACK1的表達顯著下降,，而IRE1α通路的激活水平與胰島內(nèi)的胰島素含量密切關(guān)聯(lián)。因此,，RACK1在IRE1α信號通路的生理動態(tài)調(diào)節(jié)中行使著“分子剎車”的作用,，而這一調(diào)控機制的長期失靈則可能在促發(fā)β細胞功能失調(diào)、進而加重2型糖尿病的病理過程中扮演重要的角色,。這些在細胞應(yīng)激信號通路上的發(fā)現(xiàn),，為深入了解胰島β細胞發(fā)生功能衰損的病理基礎(chǔ)提供了一個新的機制線索以及可能實施定向干預(yù)的潛在靶點。（生物谷Bioon.com）
生物谷推薦原始出處：
Sci. Signal., 26 January 2010 [DOI: 10.1126/scisignal.2000514]
A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1 Activation in Pancreatic β Cells
Yifu Qiu1, Ting Mao1, Yongliang Zhang1, Mengle Shao1, Jia You1, Qiurong Ding1, Yan Chen1, Dongmei Wu1, Dong Xie1, Xu Lin1, Xiang Gao2, Randal J. Kaufman3, Wenjun Li1*, and Yong Liu1*
1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
2 Model Animal Research Center, Nanjing University, Nanjing 210093, China.
3 Departments of Biological Chemistry and Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48105, USA.
Autophosphorylation of inositol-requiring enzyme 1 (IRE1) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic β cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1 in a glucose-stimulated or endoplasmic reticulum (ER) stress–responsive manner in pancreatic β cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1 by PP2A, thereby inhibiting glucose-stimulated IRE1 activation and attenuating IRE1-dependent increases in insulin production. Moreover, IRE1 activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1 signaling pathway in pancreatic β cells.
