immune response; NF-kB; lymphoma; signalling; lymphocyte activation; protease; proliferation
Thuille N, Wachowicz K, Hermann-Kleiter N, Kaminski S, Fresser F, Lutz-Nicoladoni C, Leitges M, Thome M, Massoumi R, Baier G (2013), PKCθ/β and CYLD Are Antagonistic Partners in the NFκB and NFAT Transactivation Pathways in Primary Mouse CD3+ T Lymphocytes, in PLoS ONE
, 8(1), x.
Pelzer Christiane, Cabalzar Katrin, Wolf Annette, Gonzalez Montserrat, Lenz Georg, Thome Margot (2013), The protease activity of the paracaspase MALT1 is controlled by monoubiquitination., in Nature immunology
, 14(4), 337-45.
Wenzel S-S, Grau M, Mavis C, Hailfinger S, Wolf A, Madle H, Deeb G, Dörken B, Thome M, Lenz P, Dirnhofer S, Hernandez-Ilizaliturri F J, Tzankov A, Lenz G (2012), MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma., in Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marion Sabrina, Mazzolini Julie, Herit Floriane, Bourdoncle Pierre, Kambou-Pene Nadège, Hailfinger Stephan, Sachse Martin, Ruland Jürgen, Benmerah Alexandre, Echard Arnaud, Thome Margot, Niedergang Florence (2012), The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles., in Developmental cell
, 23(5), 954-67.
Pelzer C, Thome M (2011), IKK alpha takes control of canonical NF-kappa B activation, in NATURE IMMUNOLOGY
, 12(9), 815-816.
Mühlethaler-Mottet A, Flahaut M, Bourloud K Balmas, Nardou K, Coulon A, Liberman J, Thome M, Gross N (2011), Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis., in Cell death & disease
, 2, 125-125.
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-kappa B activation in lymphocytes and lymphoma cell lines, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
, 108(35), 14596-14601.
Thome M, Charton JE, Pelzer C, Hailfinger S (2010), Antigen Receptor Signaling to NF-kappa B via CARMA1, BCL10, and MALT1, in COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY
, 2(9), 1-16.
CARMA1, BCL10 and MALT1 are three recently identified proteins that play an essential role in T-cell receptor- and B-cell receptor-induced lymphocyte activation and proliferation. Mice deficient in any of these three proteins show impaired antigen-dependent responses of mature T- and B-lymphocytes and are severely immunodeficient. In humans, chromosomal translocation and abnormal expression of the genes encoding BCL10 and MALT1 have been associated with constitutive activation of the transcription factor NF-?B and the formation of B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas). Morerover, oncogenic mutations in CARMA1 have been identified in patients suffering from diffuse large B-cell lymphomas (DLBCL) of the activated B-cell subtype (ABC-DLBCL). We and others have recently identified a protease activity for MALT1 that is transiently induced in activated lymphocytes in a CARMA1- and BCL10- dependent manner. Moreover, we have developed a cell-permeable inhibitor for MALT1 that leads to impaired T-cell activation in vitro and dramatically reduced cellular proliferation of B-cell lines derived from ABC-DLBCL, which showed constitutive MALT1 protease activity. Thus, the protease activity of MALT1 might be a suitable drug target for immunomodulation and/or for the treatment of particular subtypes of human lymphomas characterized by constitutive MALT1 activity. The above-mentioned findings suggest that the protease activity of MALT1 is essential for the control of lymphocyte proliferation, but the underlying molecular mechanism remains poorly understood. It is particularly unclear how the protease activity of MALT1 is initiated and terminated, which substrate proteins are cleaved by MALT1 and how cleavage of these substrates controls lymphocyte activation and proliferation. Here we propose to address these issues by (1) the identification of positive and negative regulators of MALT1 activity, (2) the characterization of the function of three recently identified MALT1 substrates and (3) the identification of novel substrates of MALT1.By the elucidation of MALT1-dependent signaling events, we expect to significantly contribute to the understanding of the molecular mechanisms that control lymphocyte activation under physiological conditions and under pathological circumstances that are associated with autoimmune diseases or lymphomas. Moreover, a better comprehension of these mechanisms could potentially allow the rational design of MALT1-inhibiting drugs with immunosuppressive or anti-lymphoma activity.