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Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

Author

Listed:
  • Fátima Cairrão

    (Universidade Nova de Lisboa)

  • Cristiana C. Santos

    (Universidade Nova de Lisboa)

  • Adrien Thomas

    (Cancer Immunology, Genentech, Inc.)

  • Scot Marsters

    (Cancer Immunology, Genentech, Inc.)

  • Avi Ashkenazi

    (Cancer Immunology, Genentech, Inc.)

  • Pedro M. Domingos

    (Universidade Nova de Lisboa)

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.

Suggested Citation

  • Fátima Cairrão & Cristiana C. Santos & Adrien Thomas & Scot Marsters & Avi Ashkenazi & Pedro M. Domingos, 2022. "Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29105-x
    DOI: 10.1038/s41467-022-29105-x
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    1. Adrien Le Thomas & Elena Ferri & Scot Marsters & Jonathan M. Harnoss & David A. Lawrence & Iratxe Zuazo-Gaztelu & Zora Modrusan & Sara Chan & Margaret Solon & Cécile Chalouni & Weihan Li & Hartmut Koe, 2021. "Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Marcella Calfon & Huiqing Zeng & Fumihiko Urano & Jeffery H. Till & Stevan R. Hubbard & Heather P. Harding & Scott G. Clark & David Ron, 2002. "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA," Nature, Nature, vol. 415(6867), pages 92-96, January.
    3. Marcella Calfon & Huiqing Zeng & Fumihiko Urano & Jeffery H. Till & Stevan R. Hubbard & Heather P. Harding & Scott G. Clark & David Ron, 2002. "Correction: Corrigendum: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA," Nature, Nature, vol. 420(6912), pages 202-202, November.
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