Luong-Gardiol Noemie, Siddiqui Imran, Pizzitola Irene, Jeevan-Raj Beena, Charmoy Mélanie, Huang Yun, Irmisch Anja, Curtet Sara, Angelov Georgi S., Danilo Maxime, Juilland Mélanie, Bornhauser Beat, Thome Margot, Hantschel Oliver, Chalandon Yves, Cazzaniga Gianni, Bourquin Jean-Pierre, Huelsken Joerg, Held Werner (2019), γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia, in Cancer Cell
, 35(4), 649-663.e10.
Mellett Mark, Meier Barbara, Mohanan Deepa, Schairer Rebekka, Cheng Phil, Satoh Takashi K., Kiefer Betina, Ospelt Caroline, Nobbe Stephan, Thome Margot, Contassot Emmanuel, French Lars E. (2018), CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17–Mediated Psoriasiform Skin Inflammation In Vivo, in Journal of Investigative Dermatology
, 138(9), 2010-2023.
Battistello Elena, Katanayeva Natalya, Dheilly Elie, Tavernari Daniele, Donaldson Maria C., Bonsignore Luca, Thome Margot, Christie Amanda L., Murakami Mark A., Michielin Olivier, Ciriello Giovanni, Zoete Vincent, Oricchio Elisa (2018), Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma, in Blood
, 131(21), 2345-2356.
Bonsignore L, Passelli K, Pelzer C, Perroud M, Konrad A, Thurau M, Stürzl M, Dai L, Trillo-Tinoco J, Del Valle L, Qin Z, Thome M (2017), A role for MALT1 activity in Kaposi’s sarcoma-associated herpes virus latency and growth of primary effusion lymphoma, in Leukemia
, 31(3), 614-624.
Jaworski Maike, Thome Margot (2016), The paracaspase MALT1: biological function and potential for therapeutic inhibition, in Cellular and Molecular Life Sciences
, 73(3), 459-473.
The protease MALT1 and its binding partners, CARMA1 and BCL10, form a complex of signaling proteins (also called the CBM complex) that is essential for the activation of the NF-?B and AP-1 transcriptional pathways in antigen-stimulated lymphocytes (Rosebeck et al., 2011; Thome et al., 2010). Genetic evidence from MALT1 knock-out mice supports the idea that MALT1 is required for the efficient generation of the adaptive immune response (Ruefli-Brasse et al., 2003; Ruland et al., 2003). Hyperactivation of this signaling pathway through activating CARMA1 mutations, on the other hand, has been associated with the development of BENTA (B-cell expansion with NF-?B and T-cell anergy) syndrome in humans (Snow et al., 2012). In addition, oncogenic activation of MALT1 has been correlated with the formation of human B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas), diffuse large B-cell lymphomas (DLBCL) and mantle cell lymphomas (Hailfinger et al., 2014; Rosebeck et al., 2011). A few years ago, we have uncovered that MALT1 has protease activity that is transiently induced in activated lymphocytes, and we have identified BCL10 and RelB as MALT1 substrates that control different aspects of lymphocyte activation (Hailfinger et al., 2011; Rebeaud et al., 2008). We could show that the viability and proliferation of B-cell lines derived from the ABC subtype of DLBCL critically depends on constitutive oncogenic MALT1 activity and the cleavage of RelB (Hailfinger et al., 2009; Hailfinger et al., 2011). Moreover, through generation of mice expressing a catalytically inactive form of MALT1, we have recently demonstrated a key role for MALT1’s protease activity in lymphocyte activation, but also in the generation of natural regulatory T cells, since these mice have a combined immunodeficiency/autoimmunity phenotype (Jaworski et al., 2014). Thus, the protease activity of MALT1 plays a key role in the immune response and the generation of lymphomas. However, the exact mechanism by which MALT1 controls immune responses, and the full elucidation of its relevant substrates remain challenging tasks. Here, we propose to (1) further characterize a recently identified MALT1 substrate in detail, by analyzing the functional consequences of its cleavage in primary lymphocytes and lymphoma cell lines and (2) to explore and validate novel candidate MALT1 substrates by proteomic approaches, in order to uncover unexplored aspects of MALT1-dependent lymphocyte biology.Through the elucidation of the physiological roles of these newly uncovered MALT1 substrates, we expect to significantly contribute to the understanding of the mechanisms that control normal lymphocyte activation and its deregulation in autoimmune diseases or lymphomas.