XBP-1 specifically promotes IgM synthesis and secretion, but is dispensable for degradation of glycoproteins in primary B cells.
Differentiation of B cells into plasma cells requires X-box binding protein-1 (XBP-1). In the absence of XBP-1, B cells develop normally, but very little immunoglobulin is secreted. XBP-1 controls the expression of a large set of genes whose products participate in expansion of the endoplasmic reticulum (ER) and in protein trafficking. We define a new role for XBP-1 in exerting selective translational control over high and sustained levels of immunoglobulin M (IgM) synthesis. XBP-1(-/-) and XBP-1(+/+) primary B cells synthesize IgM at comparable levels at the onset of stimulation with lipopolysaccharide or CpG. However, later there is a profound depression in synthesis of IgM in XBP-1(-/-) B cells, notwithstanding similar levels of micromRNA. In marked contrast, lack of XBP-1 does not affect synthesis and trafficking of other glycoproteins, or of immunoglobulin light chains. Contrary to expectation, degradation of proteins from the ER, using TCRalpha or US11-mediated degradation of class I major histocompatibility complex molecules as substrates, is normal in XBP-1(-/-) B cells. Furthermore, degradation of membrane mu was unaffected by enforced expression of XBP-1. We conclude that in primary B cells, the XBP-1 pathway promotes synthesis and secretion of IgM, but does not seem to be involved in the degradation of ER proteins, including that of mu chains themselves.
Tirosh
Boaz
B
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Iwakoshi
Neal N
NN
Glimcher
Laurie H
LH
Ploegh
Hidde L
HL
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D018899:CpG Islands / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000276:immunology; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D007147:Immunoglobulin Light Chains; D007148:Immunoglobulin mu-Chains; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse