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Open Access Green as soon as Postprint is submitted to ZB.
Oncogene-induced MALT1 protease activity drives post-transcriptional gene expression in malignant lymphomas.
Blood 142, 1985-2001 (2023)
Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB 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-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic 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 hint that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of many genes including NFKBIZ/IkBz, NFKBID/IkBNS 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 mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Nf-kappa-b; Cell-receptor; Activation; Cleavage; Regnase-1; Survival; Lymphocytes; Mechanisms; Inhibitors; Mutations
ISSN (print) / ISBN
0006-4971
e-ISSN
1528-0020
Journal
Blood
Quellenangaben
Volume: 142,
Issue: 23,
Pages: 1985-2001
Publisher
American Society of Hematology
Publishing Place
2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Signaling and Translation (SAT)
Institute of Computational Biology (ICB)
Institute of Computational Biology (ICB)
Grants
Deutsche Krebshilfe award
Deutsche Forschungsgemeinschaft
European Union's Horizon 2020 Research and Innovation Program
Federal Ministry of Education and Research-funded German Network for Bioinformatics Infrastructure
Deutsche Forschungsgemeinschaft
European Union's Horizon 2020 Research and Innovation Program
Federal Ministry of Education and Research-funded German Network for Bioinformatics Infrastructure