BLIMP-1 is a target of cellular stress and downstream of the unfolded protein response.
B lymphocyte-induced maturation protein-1 (BLIMP-1) acts during differentiation of B cells and monocytes, but was originally identified as a repressor of the IFN-beta promoter induced during viral infection. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated protein kinase (PKR). PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2alpha) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum resident PKR-homologue, is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested that BLIMP-1 might be a target of stress responses involving PERK. We demonstrate that BLIMP-1 is rapidly up-regulated during the UPR in human myeloid and B-cell lines. This response is conserved in murine B-cells and murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription. This response is dependent on an intact PERK signaling pathway, independent of new protein synthesis and blocked by an inhibitor of NF-kappaB. Our data provide evidence for a novel pathway linking cellular stress to BLIMP-1, a regulator of differentiation in macrophages and B cells.
Doody
Gina M
GM
Division of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, UK.
Stephenson
Sophie
S
Tooze
Reuben M
RM
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D004229:Dithiothreitol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000276:immunology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019892:eIF-2 Kinase / Q000276:immunology
D003513:Cycloheximide; D004268:DNA-Binding Proteins; D004229:Dithiothreitol; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D009687:Nuclear Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D019284:Thapsigargin; D014157:Transcription Factors; D019892:eIF-2 Kinase; C513258:Prdm1 protein, mouse; C087042:PRDM1 protein, human; C001329:helenalin