UPF3B modulates endoplasmic reticulum stress through interaction with inositol-requiring enzyme-1α

文献类型： 外文期刊

第一作者： Sun, Xingsheng

作者： Sun, Xingsheng;Lin, Ruqin;Lu, Xinxia;Wu, Zhikai;Qi, Xueying;Jiang, Tianqing;Jiang, Jun;Mu, Peiqiang;Chen, Qingmei;Wen, Jikai;Deng, Yiqun;Sun, Xingsheng;Lin, Ruqin;Lu, Xinxia;Wu, Zhikai;Qi, Xueying;Jiang, Tianqing;Jiang, Jun;Mu, Peiqiang;Chen, Qingmei;Wen, Jikai;Deng, Yiqun

作者机构：

期刊名称：CELL DEATH & DISEASE （ 影响因子：8.1； 五年影响因子：8.6 ）

ISSN： 2041-4889

年卷期： 2024 年 15 卷 8 期

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收录情况： SCI

摘要： The unfolded protein response (UPR) is a conserved and adaptive intracellular pathway that relieves the endoplasmic reticulum (ER) stress by activating ER transmembrane stress sensors. As a consequence of ER stress, the inhibition of nonsense-mediated mRNA decay (NMD) is due to an increase in the phosphorylation of eIF2 alpha, which has the effect of inhibiting translation. However, the role of NMD in maintaining ER homeostasis remains unclear. In this study, we found that the three NMD factors, up-frameshift (UPF)1, UPF2, or UPF3B, were required to negate the UPR. Among these three NMD factors, only UPF3B interacted with inositol-requiring enzyme-1 alpha (IRE1 alpha). This interaction inhibited the kinase activity of IRE1 alpha, abolished autophosphorylation, and reduced IRE1 alpha clustering for ER stress. BiP and UPF3B jointly control the activation of IRE1 alpha on both sides of the ER membrane. Under stress conditions, the phosphorylation of UPF3B was increased and the phosphorylated sites were identified. Both the UPF3BY160D genetic mutation and phosphorylation at Thr169 of UPF3B abolished its interaction with IRE1 alpha and UPF2, respectively, leading to activation of ER stress and NMD dysfunction. Our study reveals a key physiological role for UPF3B in the reciprocal regulatory relationship between NMD and ER stress.

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