Structural Determinants of MALT1 Protease Activity

Wiesmann, Christian; Leder, Lukas; Blank, Jutta; Bernardi, Anna; Melkko, Samu; Decock, Arnaud; D’Arcy, Allan; Villard, Frédéric; Erbel, P.; Hughes, Nicola; Freuler, Felix; Nikolay, Rainer; Alves, Juliano; Bornancin, Frédéric; Renatus, Martin

doi:10.1016/j.jmb.2012.02.018

Cited by 82 publications

(167 citation statements)

References 47 publications

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“…First, the MALT1 paracaspase dimerizes, but is retained in an inactive state by Ig3-mediated auto-inhibition. Second, substrate binding induces structural rearrangements that release the paracaspase from auto-inhibition (Wiesmann et al, 2012). The two-step activation model was confirmed by the identification of allosteric small molecule MALT1 inhibitors, which prevent the conformational rearrangement required for activation by binding to a hydrophobic pocket formed at the interface of the paracaspase and Ig3 domains ( Schlauderer et al, 2013).…”

Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 86%

“…Despite lower sequence homology, caspases are the closest homologs in mammals and the crystal structure of the MALT1 paracaspase-Ig3 domain underscores the conservation. As for classical caspases, the paracaspase domain dimerizes and Cys464 and His415 form a catalytic dyad in the active substrate bound conformation (Yu et al, 2011;Wiesmann et al, 2012). However, whereas caspases cleave substrates after Asp, MALT1 stringently requires Arg in the P1 site, which resembles the Arg/Lys specificity of metacaspases (Hachmann et al, 2012).…”

Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 99%

“…MALT1 can be auto-cleaved (Baens et al, 2014), but labeling with activity-based probes shows that MALT1 is active in its full length form Hachmann et al, 2015). Induction of catalytic activity involves conformational changes in the C-terminal Ig3 domain, which exerts an auto-inhibitory function but it is also essential for paracaspase activity (Wiesmann et al, 2012). A two-step activation model for MALT1 has been suggested.…”

Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 99%

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Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Meininger

Krappmann

2016

Biological Chemistry

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Abstract:The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigenreceptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated 'chronic' CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

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Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 86%

Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 99%

Section: Malt1 -A Scaffold and A Proteasementioning

confidence: 99%

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Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Meininger

Krappmann

2016

Biological Chemistry

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“…Upon antigen stimulation, the B-cell receptor-associated scaffold protein CARD-containing MAGUK protein 1 (CARMA1), also known as caspase recruitment domain-containing protein 11 (CARD11), is activated to recruit B-cell lymphoma/leukemia 10 (BCL10) and MALT1 forming CARMA1-BCL10-MALT1 (CBM) signallosome via two Ig domains at the amino terminus of MALT1 (refs 3,7-9). The wild-type MALT1 protein has been found to be an argininespecific protease by peptide library screening 10 and supported by structural data 11,12 . In this regard, MALT1 through its paracaspase domain exhibits proteolytic activity by targeting arginine residues of its substrates, tumour necrosis factor alphainduced protein 3 (TNFAIP3), also referred to as A20 (ref.…”

mentioning

confidence: 84%

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

Nie

McAllister-Lucas

et al. 2015

Nat Commun

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MALT1 is the only known paracaspase and is a critical mediator of B-and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.

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“…The crystal structure of the MALT1 caspase-like domain further provided clues about the mechanism of MALT1 activation: in the absence of stimulation, MALT1 is not active by itself, since the caspase-like domain is autoinhibited by its interaction with the Ig3 domain. Its activation requires a first dimerization step and a second step in which caspase substrate binding causes substantial structural reorganization, allowing the release of the caspases like domain of MALT1 from the Ig3 inhibitory domain [35]. Using mice lacking MALT1, two different studies reported impaired TCR-mediated NF-κB activation, defective lymphocyte proliferation and decreased IL-2 production (Table 1).…”

Section: Pdk1mentioning

confidence: 99%

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

Messali¹,

Génin

Weil³

2013

J Leuk

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The adaptive immune response is initiated when microbial or tumor-specific molecules are recognized by antigen receptors present at lymphocyte cell surface. Engagement of these immunoreceptors induces signaling cascades that ultimately activate the transcription factors NF-κB (Nuclear Factor-κB) and NFAT (nuclear factor of activated T-cells) responsible for the establishment of gene expression programs controlling the stimulation, proliferation and survival of activated lymphocytes. Cloning the products of three distinct translocation events found in lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) led to the identification and characterization of a novel NF-κB-activating complex following antigenic stimulation composed by the CARMA1, BCL10, and MALT1 proteins and called the CBM complex. Since the identification of this complex, other regulatory components were discovered which greatly improve our understanding of this signaling pathways.Interestingly, CBM complex activity is not only altered in MALT lymphomas but also in a subtype of activated B cell-like (ABC) of diffuse large B-cell (DLBCL) lymphoma. In this review, we described the key players involved in antigen-induced NF-κB activation and covered the recent advances in the molecular mechanisms that are responsible for the regulation of the components of the CBM complex. Understanding these mechanisms is critical for the elucidation of the role of this NF-κB signaling network in both normal and pathologic conditions and we described how dysregulation of this network leads to the uncontrolled activation of NF-κB and development of two particular subtypes of human B cell lymphomas: the MALT and the DLBCL lymphomas. DAP12) [1]. Engagement of these receptors initiate a signal-activation cascade that includes phosphorylation of two specific tyrosine residues located in the ITAM by the Src family kinases [1]. Tyrosine kinase Syk or ZAP-70 (zeta-chain-associated protein 70 kD) are then recruited to the phosphorylated ITAM through their tandem Src homology 2 (SH2) regions, initiating downstream signaling cascades that lead to the stimulation of mitogen-activated protein kinase (MAPK) activities and ultimately to the activation of the transcription factors NF-κB and NF-AT (nuclear factor of activated T-cells).An outstanding issue of lymphocyte activation was the identification of a complex of proteins comprising CARMA1, BCL10 and MALT1 (also called the CBM complex) as critical regulators of the immunoreceptor signaling pathways. In this review, we will focus on the recent advances concerning the role of the CBM function in antigen-induced NF-κB signaling and detail how this pathway may selectively become dysregulated in lymphoma. The key players of antigen-mediated NF-κB activationAntigen receptor activation initiates a phosphorylation cascade that promotes assembly of the CBM signalosome complex composed of CARMA1, BCL10, and MALT1 that ultimately activates the NEMO/ IKK complex to promote NF-κB transcription (Figure 1). In this

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Structural Determinants of MALT1 Protease Activity

Cited by 82 publications

References 47 publications

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

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