MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-κB-dependent proliferative advantage and resistance against FAS-induced cell death in B cells

Abstract

The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor B (NF- B IntroductionFour recurrent chromosomal translocations have been described in non-Hodgkin B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. Two of them, t(14;18)(q32;q21) and t(11; 18)(q21;q21), are found in 30% to 50% of extranodal MALT lymphomas. The former juxtaposes the MALT1 (MLT1 or paracaspase 1) gene to the IgH promoter region, resulting in the deregulation of MALT1 expression, whereas the latter creates a fusion between MALT1 and the inhibitor of apoptosis gene API2 (cIAP2/HIAP1). [1][2][3][4][5][6] Unlike the low-grade indolent MALT lymphomas that are dependent on the continuous presence of Helicobacter pylori, MALT lymphomas with translocations targeting the MALT1 gene can be found in cases without H pylori and are refractory to treatment against H pylori. 7,8 The other 2 much rarer translocations, t(1;14)(p22;q32) and t(1;2)(p22;p12), target the BCL10 gene on the short arm of chromosome 1. 9,10 MALT1 was independently identified as a member of the human paracaspase family and an interacting partner of B-cell lymphoma 10 (BCL10). 11 In vitro, MALT1 synergizes with BCL10 to enhance nuclear factor B activation, 12 and the association of the 2 proteins has been shown to mediate IB kinase (IKK) activation by facilitating the ubiquitinylation of the NF-B essential modulator (NEMO) by the ubiquitin-conjugating enzyme UBC13. 13 BCL10 also interacts with a group of proteins that contain an N-terminal caspase recruitment domain (CARD) domain and show overall structural homology to MAGUK (membrane-associated guanylate kinase) proteins. 14-17 These proteins were subsequently termed CARMA (CARD-containing MAGUK) proteins, of which CARMA1 (CARD11) expression is predominantly lymphoid specific. It has been shown recently that MALT1 not only interacts with BCL10 directly but also associates with CARMA1, suggesting that a complex containing MALT1, CARMA1, and BCL10 plays an important role in lymphoid cell signaling. 18 The critical function of MALT1 in lymphocyte signaling has been revealed by the analyses of MALT1-deficient mice, 19,20 whose T cells fail to proliferate in response to CD3/CD28 costimulation or to phorbol myristate acetate (PMA) and ionomycin. Similarly, B cells of MALT1 Ϫ/Ϫ mice fail to proliferate in response to immunoglobulin M (IgM), CD40, or lipopolysaccharide (LPS) stimulation. The lymphoid compartments of these mice showed severe reduction of marginal zone B cells and a lack of germinal center formation in spleens, as well as deregulated maturation of T-cell subsets in the thymus. The phenotype of MALT1-deficient mice closely resembles that of mice lacking Bcl10, in particular with respect to the lack of marginal zone B cells, and in the lack of response to T-a...

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

“…Thus, it is imperative that we gain an understanding of the precise molecular mechanisms by which API2-MALT1 functions to promote lymphomagenesis. Several recent studies have shown that expression of API2-MALT1 protects cells from apoptosis and promotes proliferation and that NF-kB activation is required for these effects (Hosokawa et al, 2004;Stoffel et al, 2004;Ho et al, 2005). Our studies demonstrate for the first time that the API2 moiety mediates oligomerization of API2-MALT1 via heterotypic interaction of the BIR1 domain with the MALT1 moiety.…”

“…This suggests that API2-MALT1 may represent a gain-offunction mutant that promotes lymphomagenesis through inappropriate NF-kB activation. In support of this notion, recent studies show that expression of API2-MALT1 protects cells from apoptosis and promotes proliferation and that NF-kB activation is required for these effects (Hosokawa et al, 2004;Stoffel et al, 2004;Ho et al, 2005). In this report, we explore the mechanism by which the API2 moiety contributes to API2-MALT1-dependent stimulation of NF-kB.…”

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

“…87 It has been proposed that chronic antigenic stimulation by H. pylori triggers T-cell-mediated B-cell growth via activation of CD40 and NF-kB pathway early in the development of gastric MALT lymphoma. In this connection, Ho et al 88 recently examined the effect of stably expressed MALT1 and API2-MALT1 in human B-cell lines on the NF-kB signaling pathway and elegantly demonstrated that cytoprotection mediated by NF-kB, once activated in a CD40-mediated immune response, is maintained and enhanced through deregulation of MALT1 or formation of API2-MALT1 fusion.…”

“…111 Two recent studies also reported that API2-MALT1 confers resistance to UV-induced and p53-dependent apoptosis. 88,112 Stoffel et al demonstrated that antiapoptotic effect of API2-MALT1 depends on its activity of NF-kB activation.…”

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

“…In mature B cells, signaling through CD40 promotes survival, somatic hyper-mutation and class-switch recombination, and the defective CD40 signaling results in hyper-IgM syndrome [31,32]. Interestingly, signaling through CD40 activates NF-jB and constitutive signaling through CD40 has been shown to promote survival of B cell lineage nonHodgkin's lymphoma [33,34]. IKK activation upon CD40 receptor ligation is mediated by TNF receptorassociated factors (TRAF) 1, 2, 5 and 6 and appear to be independent of the signaling components that connect BCR to IKK [35,36].…”