Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas

Abstract

Constitutive mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activity drives survival of malignant lymphomas addicted to chronic B-cell receptor signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. Although MALT1 scaffolding induces NF-κB-dependent survival signaling, MALT1 protease function is thought to augment NF-κB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-κB transcriptional responses but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and nonenzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data suggest that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces posttranscriptional upregulation of many genes including NFKBIZ/IκBζ, NFKBID/IκBNS, and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on an mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives posttranscriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in MALT lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and posttranscriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease-selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.