Pumilio Protects Xbp1 MRNA from Regulated Ire1-dependent Decay

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Mar 25

PMID 35332141

Authors

Fatima Cairrao

Cristiana C Santos

Adrien Le Thomas

Scot Marsters

Avi Ashkenazi

Pedro M Domingos

Affiliations

Soon will be listed here.

Abstract

The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. Here, we identify binding sites for the RNA-binding protein Pumilio in the 3'UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio binds both the Xbp1 and Xbp1 mRNAs, but only Xbp1 is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1 mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1 from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.

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