MALT1 Auto-proteolysis is Essential for NF-κB-dependent Gene Transcription in Activated Lymphocytes

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Aug 9

PMID 25105596

Citations 35

Authors

Mathijs Baens

Luca Bonsignore

Riet Somers

Charlotte Vanderheydt

Stephen D Weeks

Jenny Gunnarsson

Ewa Nilsson

Robert G Roth

Margot Thome

Peter Marynen

Affiliations

Soon will be listed here.

Abstract

Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.

Citing Articles

MALT1 substrate cleavage: what is it good for?.

Moud B, Ober F, ONeill T, Krappmann D Front Immunol. 2024; 15:1412347.

PMID: 38863711 PMC: 11165066. DOI: 10.3389/fimmu.2024.1412347.

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.

Plotnik J, Richardson A, Yang H, Rojas E, Bontcheva V, Dowell C Mol Cancer Ther. 2024; 23(7):949-960.

PMID: 38507740 PMC: 11217731. DOI: 10.1158/1535-7163.MCT-23-0518.

In silico study of polyphenols as potential inhibitors of MALT1 protein in non-Hodgkin lymphoma.

Sezer A, Mahmutovic L, Akcesme B Med Oncol. 2023; 41(1):37.

PMID: 38155268 DOI: 10.1007/s12032-023-02261-w.

Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination.

Juilland M, Alouche N, Ubezzi I, Gonzalez M, Rashid H, Scarpellino L Proc Natl Acad Sci U S A. 2023; 120(52):e2301155120.

PMID: 38109544 PMC: 10756297. DOI: 10.1073/pnas.2301155120.

MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas.

Minderman M, Lantermans H, Gruneberg L, Cillessen S, Bende R, van Noesel C Blood Cancer J. 2023; 13(1):37.

PMID: 36922488 PMC: 10017792. DOI: 10.1038/s41408-023-00809-7.

References

Sanchez-Izquierdo D, Buchonnet G, Siebert R, Gascoyne R, Climent J, Karran L . MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood. 2003; 101(11):4539-46. DOI: 10.1182/blood-2002-10-3236. View

Boatright K, Renatus M, Scott F, Sperandio S, Shin H, Pedersen I . A unified model for apical caspase activation. Mol Cell. 2003; 11(2):529-41. DOI: 10.1016/s1097-2765(03)00051-0. View

Pelzer C, Cabalzar K, Wolf A, Gonzalez M, Lenz G, Thome M . The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nat Immunol. 2013; 14(4):337-45. DOI: 10.1038/ni.2540. View

Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J . T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 2008; 9(3):263-71. DOI: 10.1038/ni1561. View

Ngo V, Davis R, Lamy L, Yu X, Zhao H, Lenz G . A loss-of-function RNA interference screen for molecular targets in cancer. Nature. 2006; 441(7089):106-10. DOI: 10.1038/nature04687. View

Che T, You Y, Wang D, Tanner M, Dixit V, Lin X . MALT1/paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-kappaB activation. J Biol Chem. 2004; 279(16):15870-6. DOI: 10.1074/jbc.M310599200. View

Willis T, Jadayel D, Du M, Peng H, Perry A, Price H . Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell. 1999; 96(1):35-45. DOI: 10.1016/s0092-8674(00)80957-5. View

Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton J . Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci U S A. 2011; 108(35):14596-601. PMC: 3167514. DOI: 10.1073/pnas.1105020108. View

Weih F, Lira S, Bravo R . Overexpression of RelB in transgenic mice does not affect I kappa B alpha levels: differential regulation of RelA and RelB by the inhibitor protein. Oncogene. 1996; 12(2):445-9. View

10.

Hara H, Wada T, Bakal C, Kozieradzki I, Suzuki S, Suzuki N . The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity. 2003; 18(6):763-75. DOI: 10.1016/s1074-7613(03)00148-1. View

11.

Tweeddale M, Lim B, Jamal N, Robinson J, Zalcberg J, Lockwood G . The presence of clonogenic cells in high-grade malignant lymphoma: a prognostic factor. Blood. 1987; 69(5):1307-14. View

12.

Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B . Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation. Immunity. 2005; 23(6):575-85. DOI: 10.1016/j.immuni.2005.10.007. View

13.

Egawa T, Albrecht B, Favier B, Sunshine M, Mirchandani K, OBrien W . Requirement for CARMA1 in antigen receptor-induced NF-kappa B activation and lymphocyte proliferation. Curr Biol. 2003; 13(14):1252-8. DOI: 10.1016/s0960-9822(03)00491-3. View

14.

Rosebeck S, Madden L, Jin X, Gu S, Apel I, Appert A . Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science. 2011; 331(6016):468-72. PMC: 3124150. DOI: 10.1126/science.1198946. View

15.

Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P . T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J. 2011; 30(9):1742-52. PMC: 3101995. DOI: 10.1038/emboj.2011.85. View

16.

Ferch U, Kloo B, Gewies A, Pfander V, Duwel M, Peschel C . Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2009; 206(11):2313-20. PMC: 2768866. DOI: 10.1084/jem.20091167. View

17.

Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D . The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol. 2008; 9(3):272-81. DOI: 10.1038/ni1568. View

18.

Baens M, Fevery S, Sagaert X, Noels H, Hagens S, Broeckx V . Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination. Cancer Res. 2006; 66(10):5270-7. DOI: 10.1158/0008-5472.CAN-05-4590. View

19.

Wu C, Ashwell J . NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008; 105(8):3023-8. PMC: 2268578. DOI: 10.1073/pnas.0712313105. View

20.

Thome M . Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol. 2008; 8(7):495-500. DOI: 10.1038/nri2338. View