Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

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 Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1spliced. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.

Proteolytic Activation of Plant Membrane-Bound Transcription Factors

“…This IRE1-dependent bZIP60 activation mechanism is similar to the previously discovered activation mechanism of the mammalian X-BOX BINDING PROTEIN 1 (XBP1) and the yeast HOMOLOGOUS TO ATF/CREB 1 (HAC1) bZIP TFs, hinting at the conservation of the UPR activation in eukaryotes. ( Yoshida et al, 2001 ; Calfon et al, 2002 ; Cairrão et al, 2022 ). For NTL5, intron retention, leading to a premature TMD-preceding stop codon, was based on a single-nucleotide polymorphism (SNP) in the third intron of the NTL5 gene in the Columbia-0 accession of Arabidopsis , leading to a permanent nuclear localization in this accession.…”

RNA-protein interactome at the Hepatitis E virus internal ribosome entry site

“…ψ-taxilin belongs to the syntaxin-binding protein family, it interacts with ATF4 and regulates the ER stress response (72). PUM1 is known to be phosphorylated by the IRE1 kinase under conditions of ER stress, it binds spliced XBP1 RNA and prevents its degradation (73). Upon ER stress, interaction between PUM1 and HEV IRESl might be protecting the later from degradation by the regulated IRE1-dependent decay (RIDD) pathway.…”

Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus

“…The IRE1a RNase domain is activated under conditions of metabolic stress (e.g. hyperglycemia, hyperlipidemia) and subsequently splices Xbp1 mRNA to generate efficient transcription factors XBP1s that upregulate the expression of ER chaperones and other UPR target genes ( 37 ) ( Figure 2 ). Research reports that activation of the IRE1a-XBP1 signaling pathway degrades insulin mRNA and activates ERAD machinery to eliminate unfolded proteins from the ER ( 38 ).…”