Abstract
The paracaspase MALT1 is a Cys-dependent, Arg-specific protease that plays an essential role in the activation and proliferation of lymphocytes during the immune response. Oncogenic activation of MALT1 is associated with the development of specific forms of B-cell lymphomas. Through specific cleavage of its substrates, MALT1 controls various aspects of lymphocyte activation, including the activation of transcriptional pathways, the stabilization of mRNAs, and an increase in cellular adhesion. In lymphocytes, the activity of MALT1 is tightly controlled by its inducible monoubiquitination, which promotes the dimerization of MALT1. Here, we describe both in vitro and in vivo assays that have been developed to assess MALT1 activity.
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References
Du MQ (2011) MALT lymphoma: many roads lead to nuclear factor-kappaB activation. Histopathology 58(1):26–38
Uren AG, O’Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM (2000) Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 6(4):961–967
Rosebeck S, Rehman AO, Lucas PC, McAllister-Lucas LM (2011) From MALT lymphoma to the CBM signalosome: three decades of discovery. Cell Cycle 10(15):2485–2496
Thome M, Charton JE, Pelzer C, Hailfinger S (2010) Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol 2(9):a003004
Staudt LM (2010) Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2(6):a000109
Ruland J, Duncan GS, Wakeham A, Mak TW (2003) Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19(5):749–758
Ruefli-Brasse AA, French DM, Dixit VM (2003) Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase. Science 302(5650):1581–1584
Thome M (2008) Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 8:495–500
Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2(10):725–734
Wiesmann C, Leder L, Blank J, Bernardi A, Melkko S, Decock A, D’Arcy A, Villard F, Erbel P, Hughes N, Freuler F, Nikolay R, Alves J, Bornancin F, Renatus M (2012) Structural determinants of MALT1 protease activity. J Mol Biol 419(1–2):4–21
Yu JW, Jeffrey PD, Ha JY, Yang X, Shi Y (2011) Crystal structure of the mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) paracaspase region. Proc Natl Acad Sci U S A 108(52):21004–21009
Snipas SJ, Wildfang E, Nazif T, Christensen L, Boatright KM, Bogyo M, Stennicke HR, Salvesen GS (2004) Characteristics of the caspase-like catalytic domain of human paracaspase. Biol Chem 385(11):1093–1098
Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ (2004) The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 14(3):289–301
Oeckinghaus A, Wegener E, Welteke V, Ferch U, Arslan SC, Ruland J, Scheidereit C, Krappmann D (2007) Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J 26(22):4634–4645
Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF, Yamaoka S, Seto M, Nunez G (2001) Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 276(22):19012–19019
Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N, Thome M (2008) The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 9:272–281
Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R (2008) T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 9(3):263–271
Vercammen D, Declercq W, Vandenabeele P, Van Breusegem F (2007) Are metacaspases caspases? J Cell Biol 179(3):375–380
Duwel M, Welteke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, Darnay BG, Ruland J, Marynen P, Krappmann D (2009) A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. J Immunol 182(12):7718–7728
Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Decaillet C, Grau M, Dorken B, Lenz P, Lenz G, Thome M (2011) Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci U S A 108(35):14596–14601
Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R (1996) Both multiorgan inflammation and myeloid hyperplasia in RelB-deficient mice are T cell dependent. J Immunol 157(9):3974–3979
Marienfeld R, May MJ, Berberich I, Serfling E, Ghosh S, Neumann M (2003) RelB forms transcriptionally inactive complexes with RelA/p65. J Biol Chem 278(22):19852–19860
Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A (2006) ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 281(27):18482–18488
Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P, Gevaert K, Beyaert R (2011) T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J 30(9):1742–1752
Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O, Akira S (2013) Malt1-induced cleavage of regnase-1 in CD4 helper T cells regulates immune activation. Cell 153(5):1036–1049
Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM (2011) Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 331(6016):468–472
Hachmann J, Snipas SJ, van Raam BJ, Cancino EM, Houlihan EJ, Poreba M, Kasperkiewicz P, Drag M, Salvesen GS (2012) Mechanism and specificity of the human paracaspase MALT1. Biochem J 443(1):287–295
Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F, Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H, Melnick A (2012) MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 22(6):812–824
Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, Salvesen GS (2003) A unified model for apical caspase activation. Mol Cell 11(2):529–541
Roschitzki-Voser H, Schroeder T, Lenherr ED, Frolich F, Schweizer A, Donepudi M, Ganesan R, Mittl PR, Baici A, Grutter MG (2012) Human caspases in vitro: expression, purification and kinetic characterization. Protein Expr Purif 84(2):236–246
Pelzer C, Cabalzar K, Wolf A, Gonzalez M, Lenz G, Thome M (2013) MALT1 protease activity is controlled by monoubiquitination. Nat Immunol 14:337–345
Hailfinger S, Lenz G, Ngo V, Posvitz-Fejfar A, Rebeaud F, Guzzardi M, Penas EM, Dierlamm J, Chan WC, Staudt LM, Thome M (2009) Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 106(47):19946–19951
Ferch U, Kloo B, Gewies A, Pfander V, Duwel M, Peschel C, Krappmann D, Ruland J (2009) Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 206(11):2313–2320
Anderson NL, Anderson NG (1978) Analytical techniques for cell fractions. XXII. Two-dimensional analysis of serum and tissue proteins: multiple gradient-slab gel electrophoresis. Anal Biochem 85(2):341–354
Acknowledgments
We thank Katrin Cabalzar, Maike Jaworski, and Chantal Decaillet for critical reading of the manuscript. Work in the Thome laboratory is supported by the Swiss National Science Foundation, the Swiss Cancer League, the foundations Leenaards and Helmut Horten, the Novartis Foundation for Medical-Biological Research, and a collaboration agreement with Ono Pharmaceuticals.
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Hailfinger, S., Pelzer, C., Thome, M. (2014). Detection and Measurement of Paracaspase MALT1 Activity. In: V. Bozhkov, P., Salvesen, G. (eds) Caspases,Paracaspases, and Metacaspases. Methods in Molecular Biology, vol 1133. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0357-3_11
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DOI: https://doi.org/10.1007/978-1-4939-0357-3_11
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