T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1

Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Zwijnaarde, Ghent, Belgium.
The EMBO Journal (Impact Factor: 10.75). 03/2011; 30(9):1742-52. DOI: 10.1038/emboj.2011.85
Source: PubMed

ABSTRACT The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-κB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-κB activation by cleaving the NF-κB inhibitor A20. Whether MALT1 protease activity is involved in other signalling pathways, and the identity of the relevant substrates, is unknown. Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes. These results indicate a novel role for MALT1 proteolytic activity in TCR-induced JNK activation and reveal CYLD cleavage as the underlying mechanism.

Download full-text


Available from: Jens Staal, Aug 09, 2015
1 Follower
  • Source
    • "The CBM signalosome further recruits signaling components such as TRAF6 for nondegradative polyubiquitination to activate the IkB kinase (IKK), resulting in IkB phosphorylation and degradation, and release of NF-kB proteins for nuclear translocation (Jiang and Lin, 2012). Formation of the CBM signalosome also enables the paracaspase activity of MALT1, which cleaves negative regulators to further enhance NF-kB activity (Coornaert et al., 2008; Hailfinger et al., 2011; Rebeaud et al., 2008; Staal et al., 2011). Nondegradative polyubiquitination that leads to association of Bcl10 with autophagosomes and feedback degradative polyubiquitination of Bcl10 may both result in its gradual degradation and homeostatic control of the pathway (Moreno-García et al., 2013; Paul et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.
    Molecular cell 09/2013; 51(6):766-79. DOI:10.1016/j.molcel.2013.08.032 · 14.46 Impact Factor
  • Source
    • "MALT1 is ubiquitinated by TRAF6 with K63-linked poly-Ub chains, which activates the NF-κB pathway [7]. Additionally, MALT1 can function as a paracaspase to cleave multiple NF-κB inhibitors, including A20 [8], RelB [9], and CYLD [10] in response to T cell antigen receptor signaling. Finally, MALT1 interacts with Caspase-8 and promotes Caspase-8–mediated FLIP L cleavage [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa-associated lymphoid tissue 1 (MALT1) as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 over-expression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion-induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets.
    Neoplasia (New York, N.Y.) 01/2013; 15(1):39-48. DOI:10.1593/neo.121362 · 5.40 Impact Factor
  • Source
    • "after arginine residues, indicating that the enzymatic cleavage activity is quite distinct from caspases, which in general require an aspartate at the P1 position (Vercammen et al., 2004). MALT1 proteolytic activity is induced upon TCR/CD28 costimulation, which promotes cleavage of the substrates BCL10, A20, CYLD, and RelB (Coornaert et al., 2008; Hailfinger et al., 2011; Rebeaud et al., 2008; Staal et al., 2011). Inhibition of MALT1 protease activity by the antagonistic tetrapeptide Z-VRPR- FMK, which was originally designed as an inhibitor of metacaspases in plants, impairs optimal NF-kB activation and inter- leukin-2 (IL-2) production in T cells (Dü wel et al., 2009; Rebeaud et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteolytic activity of the mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) paracaspase is required for survival of the activated B cell subtype of diffuse large B cell lymphoma (ABC-DLBCL). We have identified distinct derivatives of medicinal active phenothiazines, namely mepazine, thioridazine, and promazine, as small molecule inhibitors of the MALT1 protease. These phenothiazines selectively inhibit cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. Consequently, the compounds inhibit anti-apoptotic NF-κB signaling and elicit toxic effects selectively on MALT1-dependent ABC-DLBCL cells in vitro and in vivo. Our data provide a conceptual proof for a clinical application of distinct phenothiazines in the treatment of ABC-DLBCL.
    Cancer cell 12/2012; 22(6):825-37. DOI:10.1016/j.ccr.2012.11.002 · 23.89 Impact Factor
Show more