Regulated IRE1‐dependent decay participates in curtailing immunoglobulin secretion from plasma cells. (23rd December 2013)

• Record Type: Journal Article
• Authors: Benhamron, Sandrine; Hadar, Rivka; Iwawaky, Takao; So, Jae‐Seon; Lee, Ann‐Hwee; Tirosh, Boaz
• Is Part Of: European journal of immunology. Volume 44:issue 3(2014:Mar.)
• Page Start: 867
• Page End: 876
• Publication Date: 2013-12-23
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201343953
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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.</p> </abstract>