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.

Emerging roles of Jab1/CSN5 in DNA damage response, DNA repair, and cancer

“…5,83 Similarly, in pro-B cells, Jab1/CSN5 deletion leads to aberrant expression of the apoptosis-triggering protein Fas ligand. 84 A more recent study showed that by interacting with Jab1/CSN5, Fank1 could suppress apoptosis by activating the AP-1-induced anti-apoptotic pathway. 85 Consistent with these data, we found that Jab1/CSN5 deficiency resulted in early embryonic lethality owing to accelerated apoptosis.…”

New effector functions and regulatory mechanisms of BCL6 in normal and malignant lymphocytes

“…Degradation of BCL6 in B-cells is mediated though FBXO11-CUL1 E3 ligase complexes and the COPS5 protein of the COP9 signalosome [62,63]. In contrast, BCL6 is protected from degradation by Hsp90, which extends the half-life both of BCL6 protein and its mRNA [64].…”

The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver

“…To investigate the function of the CSN in different tissues, developmental stages, and experimental conditions, we have previously generated a mouse line carrying a floxed COPS5 allele . Using such a genetically engineered line, it has been established that conditional inactivation of COPS5 at the early stages of development has deleterious consequences in every tissue that has been assessed . In spite of the relevant differences in the developmental processes affecting the above tissues and cell types, a common theme emerges, as inactivation of COPS5 leads to a delay or arrest of the cell cycle, mostly at the S/G2/M interface, and to an increased apoptotic cell death .…”