title: ADAM10 regulates transcription factor expression required for plasma cell function.
abstract: A disintegrin and metalloprotease 10 (ADAM10) is a key regulator of cellular processes by shedding extracellular domains of transmembrane proteins. We have previously demonstrated that deletion of B cell expressed ADAM10 results in changes in lymphoid tissue architecture and impaired germinal center (GC) formation. In this study, mice were generated in which ADAM10 is deleted in B cells following class switch recombination (ADAM10(Δ/Δ)IgG1-cre(+/-) mice). Despite normal GC formation, antibody responses were impaired in ADAM10(Δ/Δ)IgG1-cre(+/-) mice, implicating ADAM10 in post-GC and extrafollicular B cell terminal differentiation. Surprisingly, plasma cell (PC) numbers were normal in ADAM10(Δ/Δ)IgG1-cre(+/-) mice when compared to controls. However, PCs isolated from ADAM10(Δ/Δ)IgG1-cre(+/-) mice exhibited decreased expression of transcription factors important for PC function: Prdm1, Xbp1 and Irf4. Bcl6 is a GC transcriptional repressor that inhibits the PC transcriptional program and thus must be downregulated for PC differentiation to occur. Bcl6 expression was increased in PCs isolated from ADAM10(Δ/Δ)IgG1-cre(+/-) mice at both the mRNA and protein level. These results demonstrate that ADAM10 is required for proper transcription factor expression in PCs and thus, for normal PC function.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Chaimowitz
authors.forename: Dae-Joong
authors.initials: DJ
authors.lastname: Kang
authors.forename: Lee M
authors.initials: LM
authors.lastname: Dean
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Conrad
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001426:Bacterial Proteins / Q000378:metabolism; D002452:Cell Count; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D019426:Integrases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D008164:Luminescent Proteins; D008565:Membrane Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse