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

Abstract

Abstract The unfolded protein response (UPR), as a conserved and adaptive intracellular pathway, relieves the endoplasmic reticulum (ER) stress by activating ER transmembrane stress sensors. As the 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 the maintenance of ER homeostasis remains unclear. In this study, we found that the three NMD factors, UPF1, UPF2 or UPF3B, are required to negate UPR. Among these three NMD factors, UPF3B specifically interacts 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 condition, the phosphorylation of UPF3B was increased and the phosphorylated sites were identified. Both the genetic mutation UPF3BY160D and the phosphorylation at Thr169 of UPF3B abolished its interaction with IRE1α and UPF2, respectively, led the activation of ER stress and NMD disfunction. Our study reveals a key physiological role for UPF3B in the reciprocal regulatory relationship between NMD and ER stress.