Functional analysis of cIAP2-MATL1, MALT1 and proteolytic targets in B cells

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Activation of the transcription factor nuclear factor-¿B (NF-kB) has emerged as one of the most crucial steps in mounting an effective immune response, regulating a wide panel of proteins that control the adaptive immunity. Given its central role of NF-kB in immune signaling, it is therefore not surprising that tumors have found ways to usurp this pathway to their advantage. Normally, NF-kB is transiently activated after the engagement of B cell receptor to antigens via formation of the intermediate signaling complex consisting of CARD-MAGUK protein 1 (CARMA1), B-cell lymphoma-10 (BCL10), and mucosa-associated-lymphoid-tissue lymphoma- translocation gene 1 (MALT1). However, B cell lymphomas the cells accumulate genetic lesions that alter CARD11, Bc-10, or MALT1, leading to constitutively activated NF-kB signaling. In mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, the t(11;18)(q21;q21) translocation is the most commonly found mutation and it generates a fusion protein containing cellular inhibitor of apoptosis protein 2 (cIAP2) and MALT1, leading to dramatic induction of NF-kB activation. There exists no effective treatment for translocation- positive MALT lymphoma as of now. Recently, the proteolytic activity of MALT1 and cIAP2-MALT1 has been linked to NF-kB activation by the discovery of their substrates. However, the degree of requirement for MALT1 versus cIAP2-MALT1 has not yet been compared. Nor is it known if the fusion protein has an impact on B cells. The purpose of this application is to decipher the roles of MALT1 and cIAP2-MALT1 in B lymphocyte signaling and lymphomagenesis. We propose that the proteolytic activities of both proteins are critical to their in vivo functions. In conjunction, we will explore the substrate specificities of both proteis through proteomic studies. A successful outcome would be the identification of novel MALT1 or cIAP2-MALT1 substrates, which would potentiate the development of new therapeutics to be used in the treatment of MALT lymphomas.