Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells.
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.
Institute for Drug Research, The School of Pharmacy, The Hebrew University, Jerusalem, Israel.
Sandrine
S
Benhamron
Rivka
R
Hadar
Takao
T
Iwawaky
Jae-Seon
JS
So
Ann-Hwee
AH
Lee
Boaz
B
Tirosh
D000818:Animals; D000917:Antibody Formation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007136:Immunoglobulins; D008565:Membrane Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases
ER stress; IRE1; RIDD; UPR; XBP-1; plasma cells