Functions of Bcl10 in Lymphocytes

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ABSTRACT Bcl10 (B-cell lymphoma 10) is essential for antigen receptor mediated NF-κB activation. In mice, Bcl10 deficiency results in defective lymphocyte development and proliferation, and dampened immune responses; while in humans, chromosomal translocation involving Bcl10 is associated with the development of lymphoma. Upon engagement of the T cell receptor, Bcl10 translocates with the adaptor protein MALT1, from the cytosol and becomes associated with the lipid CARMA1 in the lipid rafts. Subsequently, the CARMA1/Bcl10/MALT1 complex recruits the IκB-activating kinase to the lipid rafts, resulting in activation of the transcription factor NF-κB. Recent studies by us and others have shown that TCR engagement resulted in Bcl10 degradation and down-regulation of NF-κB activation. However, the mechanism by which Bcl10 is degraded and the biological consequences of this event are largely elusive. We recently have reported S138 as an activation dependent phosphorylation site on Bcl10 and demonstrated that substitution of S138 with alanine residue stabilized Bcl10, prolonged NF-κB activation and enhanced IL-2 production by T cells. In addition, a recent study reported that TCR engagement resulted in cleavage of Bcl10 by MALT1 to generate a Bcl10 short-form, which is important for T cell adhesion. We observed that substitution of S138 with alanine residue appeared to stabilize full-length Bcl10 but resulted in the disappearance of the short-form Bcl10. In addition, we showed that a lysosomal enzyme inhibitor stabilized the full-length Bcl10, whereas a proteasome inhibitor resulted in the accumulation of short-form Bcl10. We thus propose that phosphorylation of Bcl10 on S138 targets full-length Bcl10 degradation through lysosome pathway, and signals generation of Bcl10 short-form, which is then degraded through proteasome-dependent pathway. The molecular mechanisms by which phosphorylation of S138 on Bcl10 directs full-length Bcl10 degradation and short-form Bcl10 generation and degradation, and the biological consequences of S138 phosphorylation will be investigated in both cell line and animal systems. The proposed research should lead to an improved understanding of the mechanisms by which Bcl10 regulates NF-κB-dependent signal transduction, shed light on the molecular pathogenesis of a wide range of immunological and inflammatory disorders, and provide important new insights for designing therapeutic drugs targeted at controlling or curing these disorders.