biostudies-literatureCairrao F"la Caixa" Foundation1587https://www.ebi.ac.uk/biostudies/studies/S-EPMC8948244biostudies-literatureUnknown13(1)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^unspliced and Xbp1^spliced mRNAs, but only Xbp1^spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stresNature communicationsPumilio protects Xbp1 mRNA from regulated Ire1-dependent decay.PMC8948244LCF/PR/HR17/52150018Le Thomas AMarsters SAshkenazi ACairrao FSantos CCDomingos PMfalsePumilio protects Xbp1 mRNA from regulated Ire1-dependent decay.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^unspliced and Xbp1^spliced mRNAs, but only Xbp1^spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stres2022-01-01T00:00:00Z2022 Mar2025-04-19T00:41:28.558Z2025-04-07T11:45:31.556ZS-EPMC89482443533214110.1038/s41467-022-29105-x