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

Staal, Jens; Driege, Yasmine; Bekaert, Tine; Demeyer, Annelies; Muyllaert, David; Damme, Petra Van; Gevaert, Kris; Beyaert, Rudi

doi:10.1038/emboj.2011.85

Cited by 197 publications

(209 citation statements)

References 53 publications

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“…However, normal antigen receptor signaling recruits the kinase TAK1 to the CBM complex and thus initiates the AP-1 activation cascade (42), and BCL10 can act as a JNK-interacting protein that allows recruitment of JNK2 for c-Jun phosphorylation (43). In addition, the physiological assembly of CBM complexes induces proteolytic activity of the MALT1 paracaspase, which can cleave and inactivate the negative JNK regulator CYLD to enforce the signal for AP-1 activation (44)(45)(46)(47)(48). It is likely similar that those mechanisms would also be engaged by oncogenic CARD11 mutants, but this hypothesis remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Knies

Alankus

Weilemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

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Section: Discussionmentioning

confidence: 99%

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Knies

Alankus

Weilemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Reactive oxygen or nitrogen species can also post-translationally modify DUBs as illustrated by the hydrogen peroxide-mediated modification of Cezanne (Enesa et al, 2008a). Furthermore, some DUBs such as USP1 and ATXN3 are inactivated by autoproteolytic cleavage, whereas CYLD and A20 are inactivated through the action of other proteases (Huang et al, 2006;Mauri et al, 2006;Coornaert et al, 2008;Staal et al, 2011).…”

Section: Enzymatic Roles and Regulation Of Dubsmentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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“…B-cell receptor stimulation by bacterial antigens such as Helicobacter pylori leads to constitutive activation of MALT1 in the CBM signallosomes and cleavage of these substrates. While the full consequence of these cleavage events is not yet understood, each of the known substrates plays a prominent role in regulating NF-kB 16 and JNK 14 signalling. MALT1-null animals exhibit B-and T-cell functional defects 17 .…”

mentioning

confidence: 99%

“…The known substrates of API2-MALT1 include A20 (ref. 4), NIK 37 and CYLD 14 . Consistent with the observations in API2-MALT1 cleavage of NIK 37 , we hypothesized that given the retention of the BIR domains in the API2-MALT1 fusions the BIR domains of API2 could recruit atypical substrates to the chimeric API2-MALT1 proteins and that these could be cleaved by the C-terminal MALT1 paracaspase to promote MALT lymphomagenesis via hitherto unknown mechanisms.…”

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confidence: 99%

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

Cited by 197 publications

References 53 publications

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Deubiquitinases in cancer: new functions and therapeutic options

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

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