Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells

Sandrine Benhamron, Rivka Hadar, Takao Iwawaky, Jae Seon So, Ann Hwee Lee, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Inositol-requiring enzyme 1 (IRE1) is a kinase and ribonuclease that executes the splicing of X box binding protein 1 (XBP-1) mRNA in response to the accumulation of unfolded protein in the ER, a signal cascade termed the unfolded protein response. Recently, IRE1 has been implicated in mRNA and miRNA cleavage and degradation, a pathway termed regulated IRE1-dependent decay (RIDD). Deletion of XBP-1 in the liver and pancreas strongly enhances RIDD by upregulating IRE1 protein levels and enhancing its ribo-nuclease activity. Because XBP-1 is essential for generating plasma cells with developed secretory capacity, we sought to evaluate the contribution of RIDD to this regulation. Mice were conditionally deleted for XBP-1 and/or IRE1 in their B-cell lineage. Similarly to the liver, deletion of XBP-1 induces IRE1 expression in LPS-treated B cells. In vitro, IRE1 cleaves the mRNA of secretory μ chains, which explains the reduction in secretory μ mRNA and its synthesis in XBP-1 KO plasma cells. In accordance, the IgM response is partially restored in XBP-1/IRE1 double KO mice relative to XBP-1 KO mice. Interestingly, the IgG1 response is reduced to a similar level in XBP-1 KO, IRE1 KO, and their double knockout animals. Our data demonstrate a specific contribution by RIDD in curtailing immunoglobulin synthesis and secretion.

Original languageAmerican English
Pages (from-to)867-876
Number of pages10
JournalEuropean Journal of Immunology
Volume44
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • ER stress
  • IRE1
  • Plasma cells
  • RIDD
  • UPR
  • XBP-1

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