Genetic errors of the human caspase recruitment domain–B-cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity

Abstract

Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These three CARD-BCL10-MALT1 (CBM) complexes activate NF-κB in both the innate and adaptive arms of immunity. Human inherited defects of the three components of the CBM complex, including the two adaptors CARD9 and CARD11 and the two core components BCL10 and MALT1, have recently been reported. Bi-allelic loss-of-function (LOF) mutant alleles underlie several different immunological and clinical phenotypes, which can be assigned to two distinct categories. Isolated invasive fungal infections, of unclear cellular basis, are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1 and BCL10 deficiencies. Interestingly, humans with these mutations have some features in common with the corresponding knockout mice, but other features are different between humans and mice. Moreover, germline and somatic gain-of-function (GOF) mutations of MALT1, BCL10 and CARD11 have also been found in other patients with lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including LOF and GOF mutations, highlights the contribution of each of the components of the CBM to human immunity.

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

“…In humans and mice, genetic defects in components of the antigen receptor signaling pathway result in immunodeficiency syndromes in which the failure to mount an effective immune response confers enhanced susceptibilities to infection and impaired clearance of pathogens (3,4).…”

MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage

“…As such, the complex plays a critical role in the adaptive immune system; deficiencies in any of the three components, in both humans and mice, lead to impaired lymphocyte activation in the face of antigenic challenge and to susceptibility to infection (Perez de Diego et al, 2015; Thome, 2004; Turvey et al, 2014). MALT1 is viewed as the effector protein of the CBM complex and operates through two distinct mechanisms (Afonina et al, 2015).…”

Molecular Determinants of Scaffold-induced Linear Ubiquitinylation of B Cell Lymphoma/Leukemia 10 (Bcl10) during T Cell Receptor and Oncogenic Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling

“…The clearance of pathogens by the adaptive immune system relies upon signaling pathways that activate the NF-B transcription factor following the recognition of foreign antigens by the T cell receptor (TCR) 4 and B cell receptor (BCR) complexes on lymphocytes (1,2). NF-B controls the induction of programs of gene expression required for lymphocyte activation, proliferation, and survival.…”

“…NF-B controls the induction of programs of gene expression required for lymphocyte activation, proliferation, and survival. The failure to signal to NF-B downstream of antigen receptor engagement can result in immunodeficiency and the increased susceptibility to infectious disease (3,4).…”