MALT1 protease activity in primary effusion lymphoma

The activation, proliferation and survival of lymphocytes depend on the antigen receptor-induced formation of cytoplasmic signaling complexes that control specific transcriptional pathways. The protease MALT1 has an essential role in lymphocyte activation and lymphoma development [1, 2]. Upon antigen receptor triggering, MALT1 is recruited to the so-called CBM complex, formed by the assembly of the proteins CARMA1 (also known as CARD11), BCL-10 and MALT1. The CBM complex promotes the activation of the transcription factor NF-κB1 (also known as the classical NF-κB pathway) by two means: first, it allows MALT1 to recruit and activate the IκB kinase (IKK)-complex, which phosphorylates and thereby inactivates the NFκB inhibitor IκB, and second, it promotes the MALT1dependent cleavage of proteins with negative regulatory roles in the NF-κB1 pathway, namely A20 and RelB (Figure 1A and 1B). MALT1 inhibitors already showed promise in preclinical lymphoma studies [3] and recent findings from our laboratory now suggest they may also be efficient against virally induced lymphomas [4]. Over the last few years, constitutive MALT1 activation has been recognized as a common feature of various B cell malignancies and B cell proliferative diseases, such as diffuse large B-cell lymphoma of the activated B-cell subtype (ABC DLBCL), mantle cell lymphoma (MCL), MALT lymphoma and BENTA syndrome (Figure 1A and 1C) [2]. Recently, the protooncogenic role of MALT1 has been extended to several T cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL), peripheral T cell lymphoma (PTCL) and Sézary syndrome (Figure 1B) [2, 5]. The addiction of these lymphomas to MALT1’s protease and scaffold activity is mainly due to oncogenic somatic mutations that alter the activity or expression of components of the CBM complex itself or of its upstream signaling events, and/or to the recognition of self-antigens [2], as depicted in Figure 1 (red stars indicate presence of mutations). A recurrent mutation found in MALT lymphoma is a chromosomal translocation that generates a MALT1-API2 fusion protein (Figure 1C). This fusion protein constitutively activates NF-κB1 through MALT1’s scaffold function and cleavage of classical MALT1 substrates. The API2 moiety of the MALT1-API2 fusion protein additionally recruits the kinase NIK and the tumor suppressor LIMA-1, whose cleavage promotes activation of the NF-κB2 pathway and cell growth, respectively [1, 2]. Lymphoid tumors can also be triggered by oncogenic herpes viruses, such as Epstein-Barr virus (EBV, also known as HHV-4), associated with Hodgkin and Burkitt lymphomas, or Kaposi’s sarcoma herpes virus (KSHV, also known as HHV-8), which induces Editorial