JAB1 is essential for B cell development and germinal center formation and inversely regulates Fas ligand and Bcl6 expression.
Jun activation domain-binding protein 1 (JAB1) regulates ubiquitin-dependent protein degradation by deneddylation of cullin-based ubiquitin ligases and, therefore, plays a central role in regulating proliferation and apoptosis. Because these processes are decisive for B cell development, we investigated JAB1 functions in B cells by establishing a mouse strain with a B cell-specific JAB1 deletion. We show that JAB1 is essential for early B cell development, because the ablation of JAB1 expression blocks B cell development between the pro-B and pre-B cell stages. Furthermore, JAB1 deletion leads to aberrant expression of the apoptosis-triggering protein Fas ligand in pro-B cells. Concomitant B cell-specific overexpression of the antiapoptotic protein Bcl2 partially reverses the block in B cell development; rescued JAB1-deficient B cells reach the periphery and produce protective class-switched Abs after Borrelia burgdorferi infection. Interestingly, B cell-rescued mice exhibit no germinal centers but a striking extrafollicular plasma cell accumulation. In addition, JAB1 is essential for Bcl6 expression, a transcriptional repressor required for germinal center formation. These findings identify JAB1 as an important factor in checkpoint control during early B cell development, as well as in fate decisions in mature Ag-primed B cells.
Microbiological Institute-Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany.
Selina
S
Sitte
Joachim
J
Gläsner
Julia
J
Jellusova
Florian
F
Weisel
Martina
M
Panattoni
Ruggero
R
Pardi
André
A
Gessner
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D000075686:COP9 Signalosome Complex; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000276:immunology; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010447:Peptide Hydrolases / Q000276:immunology / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex