BCL10 protein

BCL10 was originally identified from a recurrent breakpoint (1p22) in mucosa-associated lymphoid tissue (MALT) B-cell lymphomas harboring the translocation t(1;14)(p22;q32), resulting in overexpression of BCL10 (Willis TG et al. 1999). This observation, in conjunction with the finding that BCL10 can strongly induce NF-κB activation, highlights its involvement in NF-κB signaling. BCL10 is a ~27 kDa protein containing an N-terminal CARD domain and a C-terminal serine/threonine-rich region. The protein is encoded by the gene of the same name located on chromosome 1p22.3.

BCL10 is a ~27 kDa protein that contains an N-terminal CARD domain and a C-terminal serine/threonine-rich region. Through CARD-CARD interactions, BCL10 can oligomerize with other CARD-containing proteins, including CARD9, CARD10, CARD11 and CARD14 ( Bertin J et al. 2000; Wang L et al. 2001). and MALT1 to form various CBM complexes. Together, these complexes regulate both innate and adaptive immune processes in different cell types, although here the lymphoid role is in the foreground. Like CARD11, BCL10 is also subject to various post-translational modifications that regulate CBM assembly and signaling and can form highly ordered filamentous structures [summarized in (Gehring T et al. 2018).

Deletion of Bcl10 in mice leads to partial embryonic lethality (1/3 die) due to problems with neural tube closure during development. Apart from this particular phenotype, Bcl10-/- mice were immunodeficient and generally resembled Card11-/- mice. Similar to CARD11-deficient mice, Bcl10-/- mice also exhibited panhypogammaglobulinemia and impaired T-dependent humoral responses. Loss-of-function mutations of BCL10 cause a combined immunodeficiency. Lymphocyte counts are generally normal, but B and T cells mostly showed a naïve phenotype with an associated reduction in memory B and T cells and a marked absence of Tregs.

BCL10 deficiency should be considered when a patient is found to have extensive immunodeficiencies/CID affecting both innate (fibroblasts) and adaptive immunity (B and T cells), particularly when a patient has severe inflammatory diseases of the gastrointestinal (GI) tract and respiratory tract. Diagnostic clues include hypogammaglobulinemia, lack of Tregs and the presence of predominantly naïve B and T cells with reduced memory compartments. Sequencing of BCL10 should confirm the diagnosis, but functional evaluation of new BCL10 variants may be required to clearly link the variant to the clinical phenotype. To date, only one patient has been described who died of respiratory failure at the age of three years.

1. Goel S et al. (2022) CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited. J Clin Immunol 42:336-349.
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3. Ruland J et al. (2001) Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappa-B and neural tube closure. Cell 104: 33-42.
4. Xue L et al. (2003) Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immune 4: 857-865.