BLIMP‐1 is a target of cellular stress and downstream of the unfolded protein response

• Published in: European Journal of Immunology 2006-06, Vol.36 (6), p.1572-1582
• Main Authors: Doody, Gina M., Stephenson, Sophie, Tooze, Reuben M.
• Format: Article
• Language: English
• Subjects: Animals; B cell; B-Lymphocytes - immunology; Cell differentiation; Cycloheximide - pharmacology; Dithiothreitol - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; eIF-2 Kinase - immunology; Enzyme Inhibitors - pharmacology; Eukaryotic Initiation Factor-2 - immunology; Gene regulation; HeLa Cells; HL-60 Cells; Humans; Macrophage; Macrophages - immunology; Mice; Mice, Inbred C57BL; Nuclear Proteins - genetics; Nuclear Proteins - immunology; Positive Regulatory Domain I-Binding Factor 1; Protein Folding; Protein Synthesis Inhibitors - pharmacology; Regulatory Factor X Transcription Factors; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; Repressor Proteins - immunology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Sesquiterpenes - pharmacology; Sesquiterpenes, Guaiane; Signal Transduction; Thapsigargin - pharmacology; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - immunology
• ISSN: 0014-2980; 1521-4141; 1365-2567
• DOI: 10.1002/eji.200535646

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‐β 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 (eIF2α) 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‐κB. Our data provide evidence for a novel pathway linking cellular stress to BLIMP‐1, a regulator of differentiation in macrophages and B cells.