Pharmacologic Inhibition of MALT1 Protease by Phenothiazines as a Therapeutic Approach for the Treatment of Aggressive ABC-DLBCL

Nagel, Daniel; Spranger, Stefani; Vincendeau, Michelle; Grau, Michael; Raffegerst, Silke; Kloo, Bernhard; Hlahla, Daniela; Neuenschwander, Martin; Kries, Jens Peter von; Hadian, Kamyar; Dörken, Bernd; Lenz, Peter; Lenz, Georg; Schendel, Dolores J.; Krappmann, Daniel

doi:10.1016/j.ccr.2012.11.002

Cited by 202 publications

(249 citation statements)

References 45 publications

(66 reference statements)

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“…2D). This was also true when MALT1 enzyme activity was blocked with the tetrapeptide protease inhibitor zVRPR.fmk or with Mepazine (Nagel et al, 2012;Rebeaud et al, 2008), suggesting that HOIL1 cleavage results from MALT1 protease activity ( Fig. 2E,F; Fig.…”

Section: Resultsmentioning

confidence: 83%

“…The resulting aberrant activation of NF-κB and of MALT1 counteracts cell death and promotes unlimited growth (Shaffer et al, 2012). In return, ABC DLBCL cells develope a profound addiction to the CBM-NF-κB nexus and to MALT1 catalytic activity (Ferch et al, 2009;Fontan et al, 2012;Hailfinger et al, 2009;Nagel et al, 2012;Ngo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

Douanne

Gavard

Bidère

2016

Journal of Cell Science

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Antigen-receptor-mediated activation of lymphocytes relies on a signalosome comprising CARMA1 (also known as CARD11), BCL10 and MALT1 (the CBM complex). The CBM activates nuclear factor κB (NF-κB) transcription factors by recruiting the 'linear ubiquitin assembly complex' (LUBAC), and unleashes MALT1 paracaspase activity. Although MALT1 enzyme shapes NF-κB signaling, lymphocyte activation and contributes to lymphoma growth, the identity of its substrates continues to be elucidated. Here, we report that the LUBAC subunit HOIL1 (also known as RBCK1) is cleaved by MALT1 following antigen receptor engagement. HOIL1 is also constitutively processed in the 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which exhibits aberrant MALT1 activity. We further show that the overexpression of MALT1-insensitive HOIL1 mitigates T-cell-receptor-mediated NF-κB activation and subsequent cytokine production in lymphocytes. Thus, our results unveil HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1. This cleavage could therefore constitute an appealing therapeutic target for modulating immune responses.

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Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

Douanne

Gavard

Bidère

2016

Journal of Cell Science

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“…Although the specific importance of MALT1-dependent A20, CYLD, and RelB processing in the development of MS remains to be determined, the fact that A20 deficiency in mice is associated with autoimmunity (24-29) and the association between single-nucleotide polymorphisms in the human A20 gene locus and multiple autoimmune diseases, including MS (30-32), suggest a potential role for A20 cleavage. Very recently, small compound MALT1 inhibitors that inhibit T cell activation and suppress the growth of the MALT1-dependent activated B cell subtype of diffuse large B cell lymphoma in vitro and in vivo were described (33,34). Therefore, it will be of high interest to analyze the effect of such inhibitors on the development of EAE and other T cell-mediated autoimmune pathologies.…”

Section: Discussionmentioning

confidence: 99%

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Guire

Wieghofer

Elton

et al. 2013

The Journal of Immunology

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The paracaspase MALT 1 is a major player in lymphocyte activation and proliferation. MALT1 mediates Ag-induced signaling to the transcription factor NF-κB by functioning both as a scaffold protein and cysteine protease. We studied the role of MALT1 in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. MALT1-knockout mice did not develop any clinical symptoms of EAE. In addition, lymphocyte and macrophage infiltration into the spinal cord was absent in MALT1-knockout mice, as were demyelination and proinflammatory gene expression. Adoptive transfer experiments showed that MALT1 deficiency in splenocytes is sufficient for EAE resistance. Moreover, autoreactive T cell activation was severely impaired in MALT1-deficient T cells, suggesting the inability of MALT1-deficient effector T cells to induce demyelinating inflammation in the CNS. Finally, the MALT1 substrates A20 and CYLD were completely processed in wild-type T cells during EAE, which was partially impaired in MALT1-deficient T cells, suggesting a contribution of MALT1 proteolytic activity in T cell activation and EAE development. Together, our data indicate that MALT1 may be an interesting therapeutic target in the treatment of multiple sclerosis.

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“…7 Melnick told SciBX last week that the licensing status of his team's series of MALT1 inhibitors is undisclosed.…”

Section: Fermenting Strengthmentioning

confidence: 99%

Germinating MALT1

Cain¹

2014

Science-Business eXchange

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Pharmacologic Inhibition of MALT1 Protease by Phenothiazines as a Therapeutic Approach for the Treatment of Aggressive ABC-DLBCL

Cited by 202 publications

References 45 publications

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Germinating MALT1

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