JAB1 is essential for B cell development and germinal center formation and inversely regulates Fas ligand and Bcl6 expression.

Abstract

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.

• Authors: Selina Sitte, Joachim Gläsner, Julia Jellusova, Florian Weisel, Martina Panattoni, Ruggero Pardi, André Gessner
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 6 Pg. 2677-86 (Mar 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22327073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bcl6 protein, mouse
• DNA-Binding Proteins
• Fas Ligand Protein
• Intracellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins c-bcl-6
• Peptide Hydrolases
• Cops5 protein, mouse
• COP9 Signalosome Complex

Topics

• Animals
• B-Lymphocytes (cytology, immunology)
• COP9 Signalosome Complex
• Cell Differentiation (immunology)
• Cell Separation
• DNA-Binding Proteins (biosynthesis, immunology)
• Enzyme-Linked Immunosorbent Assay
• Fas Ligand Protein (biosynthesis, immunology)
• Flow Cytometry
• Germinal Center (cytology, immunology)
• Immunoblotting
• Intracellular Signaling Peptides and Proteins (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Peptide Hydrolases (immunology, metabolism)
• Precursor Cells, B-Lymphoid (immunology, metabolism)
• Proto-Oncogene Proteins c-bcl-6
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction