title: IRF4 Deficiency Leads to Altered BCR Signalling Revealed by Enhanced PI3K Pathway, Decreased SHIP Expression and Defected Cytoskeletal Responses.
abstract: The graded expression of transcription factor interferon regulatory factor 4 (IRF4) regulates B cell development and is critical for plasma cell differentiation. However, the mechanisms, by which IRF4 elicits its crucial tasks, are largely unknown. To characterize the molecular targets of IRF4 in B cells, we established an IRF4-deficient DT40 B cell line. We found that in the absence of IRF4, the expression of several molecules involved in BCR signalling was altered. For example, the expression of B cell adaptor for PI3K (BCAP) was upregulated, whereas the SHIP (SH2-containing Inositol 5?-Phosphatase) expression was downregulated. These molecular unbalances were accompanied by increased BCR-induced calcium signalling, attenuated B cell linker protein (BLNK) and ERK activity and enhanced activity of PI3K/protein kinase B (Akt) pathway. Further, the IRF4-deficient cells showed dramatically diminished cytoskeletal responses to anti-IgM cross-linking. Our results show that IRF4 has an important role in the regulation of BCR signalling and help to shed light on the molecular mechanisms of B cell development and germinal centre response.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.|Turku Doctoral Programme of Biomedical Sciences, University of Turku, Turku, Finland.
authors.forename: P M
authors.initials: PM
authors.lastname: Budzyńska
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Niemelä
authors.affiliation: Institute of Biomedicine, Department of Pathology, University of Turku, Turku, Finland.
authors.forename: A V
authors.initials: AV
authors.lastname: Sarapulov
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: M K
authors.initials: MK
authors.lastname: Kyläniemi
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: K-P
authors.initials: KP
authors.lastname: Nera
authors.affiliation: The Finnish Microarray and Sequencing Center, Turku Centre for Biotechnology, Turku, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Junttila
authors.affiliation: The Finnish Microarray and Sequencing Center, Turku Centre for Biotechnology, Turku, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Laiho
authors.affiliation: Institute of Biomedicine, Department of Pathology, University of Turku, Turku, Finland.
authors.forename: P K
authors.initials: PK
authors.lastname: Mattila
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Alinikula
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Lassila
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000502:physiology*; D020013:Calcium Signaling / Q000235:genetics; D002460:Cell Line; D002645:Chickens; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D055786:Gene Knockout Techniques; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D000072377:Syk Kinase; D000099218:Interferon Regulatory Factor-4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D030161:Avian Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D011505:Protein-Tyrosine Kinases; D011947:Receptors, Antigen, B-Cell; D000072377:Syk Kinase; C113939:B cell linker protein; C435124:IRF4 protein, Gallus gallus; D000099218:Interferon Regulatory Factor-4