cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas

Abstract

The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphomas is associated with independent chromosomal translocations that lead to the upregulation of either BCL10 or MALT1 or the generation of a fusion protein, cIAP2-MALT1. While both BCL10 and MALT1 are critically involved in antigen receptormediated NF-κB activation, the role of cIAP2 is not clear. Here we show that cIAP2 is a ubiquitin ligase (E3) of BCL10 and targets it for degradation, inhibiting antigen receptor-mediated cytokine production. cIAP2-MALT1 lacks E3 activity, and concomitantly, the BCL10 protein is stabilized in MALT lymphomas harboring this fusion. Furthermore, BCL10 and cIAP2-MALT1 synergistically activate NF-κB. These results reveal cIAP2 as an inhibitor of antigenic signaling and implicate its dysfunction in MALT lymphomas. IntroductionInhibitor of apoptosis proteins (IAPs) are a family of evolutionarily conserved proteins that regulate apoptosis and other cellular processes (1, 2). IAPs contain 1-3 characteristic baculoviral IAP repeat (BIR) motifs, which can directly bind to and inhibit caspases, the central executioner proteases of apoptosis (3). This inhibitory effect of IAPs on caspases is counteracted during apoptosis by death inducers such as mammalian Smac/DIABLO (4-6). However, some IAPs, including cellular IAP1 (cIAP1) and cIAP2, are poor inhibitors of caspases, and they may have important functions in addition to or instead of inhibiting apoptosis. cIAPs and several other IAPs also contain a RING domain, which possesses ubiquitin ligase (E3) activity that may mediate the degradation of themselves and proapoptotic proteins such as Smac/DIABLO (7-9). cIAP1 targets the antiapoptotic molecule TRAF2 for degradation and thus plays a role in promoting apoptosis (10).cIAP2 is implicated in the mucosa-associated lymphoid tissue (MALT) lymphomas; this presents a definitive example of the involvement of IAPs in human diseases. MALT lymphomas are the most common type of human lymphomas that arise in extranodal sites. They affect virtually every organ in the human body; the majority occur in the stomach (11,12). The pathogenesis of MALT lymphomas is specifically associated with at least 3 independent chromosomal translocations. Two translocations, t(1;14)(q22;q32) and t(14;18)(q32;q21), result in the upregulation of BCL10 (an adaptor protein with a caspase recruitment domain, or CARD) and MALT1 (a paracaspase related to caspases), respectively, because of the juxtaposition of the corresponding genes with the Ig heavy chain locus (13-17). The third and most common translocation, t(11;18)(q21;q21), generates a fusion protein between cIAP2 and MALT1 (18)(19)(20). MALT lymphomas with these distinct translocations present no apparent difference in their clinical and pathological features, indicating that there may be a unifying molecular mechanism for the tumors. Indeed, both BCL10 and MALT1 play a critical role in antigen receptor-mediated lymphocyte proliferation and signaling to NF-κB, which controls the expression of genes critica...

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

“…Rather, our data suggest that API2(1-441) slightly enhances Bcl10-mediated and CARMA1-mediated NF-kB activation. This finding is consistent with a recent report in which Hu et al (2006) proposed that the binding of Bcl10 to the BIR region of wild-type API2 leads to Bcl10 ubiquitination and degradation. According to this model, API2(1-441) could competitively inhibit Bcl10 interaction with wildtype API2.…”

“…For example, a recent report suggested that the BIR1 domain of API2 might contribute to API2-MALT1-dependent NF-kB activation by promoting association of the fusion protein with membrane lipid rafts (Baens et al, 2006). Another recent report demonstrated that the API2 BIR1 interacts with Bcl10 (Hu et al, 2006). These authors suggested that binding of API2-MALT1 to Bcl10 may promote lymphocyte proliferation by protecting Bcl10 from wild-type API2-mediated ubiquitination and degradation (Hu et al, 2006).…”

“…Another recent report demonstrated that the API2 BIR1 interacts with Bcl10 (Hu et al, 2006). These authors suggested that binding of API2-MALT1 to Bcl10 may promote lymphocyte proliferation by protecting Bcl10 from wild-type API2-mediated ubiquitination and degradation (Hu et al, 2006). Further studies are needed to assess the relative contribution of BIR1-mediated oligomerization, TRAF2 binding, lipid raft association and Bcl10 binding to API2-MALT1 oncogenic function.…”

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

“…Resistance to apoptosis accompanied by uncontrollable cell division could promote growth of tumor mass in the nude mice. This working model is also supported by the knowledge that a G 2 /M checkpoint defect promotes tumorigenesis (3) and that there is close association of up-regulation of three such antiapoptotic proteins, Bcl-xL, XIAP, and cIAP2, with constitutive activation of NF-B and resistance to apoptosis in a variety of human malignancies (45)(46)(47)(48)(49)(50).…”

The pathogenesis of MALT lymphomas: where do we stand?

“…27 Hosokawa et al 57 failed to demonstrate an interaction with endogenous BCL10, possibly because their fusion variant contained only the second Ig domain of MALT1 which might not be sufficient to engage BCL10. But Hu et al 58 showed that overexpressed BCL10 interacts with the BIR domains of the API2-MALT1 fusion, and RNA-mediated interference experiments further indicated that BCL10, at least in HeLa cells, is crucial for API2-MALT1 to activate NF-kB. These discrepancies might rise from the kind of API2-MALT1 fusion variant used, the cell systems in which the experiments were performed and the BCL10 expression level (endogenous or overexpressed) and demand clarification.…”