PDF(Pubmed)
Abstract：
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 eIF2α, 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-1α (IRE1α). This interaction inhibited the kinase activity of IRE1α, abolished autophosphorylation, and reduced IRE1α clustering for ER stress. BiP and UPF3B jointly control the activation of IRE1α 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 IRE1α 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.
摘要：
未折叠蛋白反应(UPR)是一种保守的和适应性的细胞内途径,其通过激活内质网(ER)跨膜应激传感器来缓解内质网(ER)应激。作为ER压力的结果，无义介导的mRNA衰减（NMD）的抑制是由于eIF2α磷酸化的增加，具有抑制翻译的作用。然而,NMD在维持ER稳态中的作用尚不清楚.在这项研究中,我们发现这三个NMD因素，上移码(UPF)1、UPF2或UPF3B，被要求否定普遍定期审议。在这三个NMD因素中，只有UPF3B与需要肌醇的酶1α（IRE1α）相互作用。这种相互作用抑制了IRE1α的激酶活性，取消了自磷酸化，并减少了ER压力的IRE1α聚类。BiP和UPF3B共同控制ER膜两侧IRE1α的活化。在应力条件下，UPF3B的磷酸化增加，并鉴定了磷酸化位点。UPF3B在Thr169的UPF3BY160D基因突变和磷酸化分别消除了其与IRE1α和UPF2的相互作用，导致内质网应激和NMD功能障碍的激活。我们的研究揭示了UPF3B在NMD和ER应激之间的相互调节关系中的关键生理作用。
