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Malt1 protease is critical in maintaining function of Treg cells and may be a therapeutic target for anti-tumor immunity

ABSTRACT: We report that the paracaspase Malt1 is required for the development and function of Treg cells. By generating Malt1 conditional knockout and protease dead mutant mice, we found Malt1-loss in Treg cells would lead to early-onset lethal autoimmune disease and the mice would die within 40 days after birth. Interestingly, mice with Treg specific inhibition of Malt1 protease activity develop spontaneous inflammatory disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE124089 | GEO | 2018/12/20

REPOSITORIES: GEO

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MALT1 protease activity controls the expression of inflammatory genes in keratinocytes upon Zymosan stimulation

2015-10-24 | GSE74297 | GEO

MALT1 protease activity controls the expression of inflammatory genes in keratinocytes upon Zymosan stimulation

Project description:The protease activity of the paracaspase MALT1 plays an important role in antigen receptor-mediated lymphocyte activation by controlling the activity of the transcription factor NF-kB and is thus essential for the expression of inflammatory target genes. MALT1 is not only present in cells of the hematopoietic lineage, but is ubiquitously expressed. Here we report that Zymosan or S. aureus stimulation induced MALT1 protease activity in human primary keratinocytes. Human primary keratinocytes were treated for 8 h with solvent control (DMSO), PMA/Ionomycin (P/I) or P/I with MALT1-inhibitor LVSR-fmk. Three biological replicates of each stimualtion were analyzed for gene expression profiles.

2015-10-24 | E-GEOD-74297 | biostudies-arrayexpress

Oncogene-induced MALT1 protease activity drives post-transcriptional gene expression in malignant lymphomas

Project description:Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. By cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of genes like NFKBIZ/IkBz, NFKBID/IkBNS and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes will provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.

2023-08-25 | GSE215792 | GEO

Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation

Project description:The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-kB activation, and its proteolytic domain cleaves negative NF-kB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T-cell and innate-like B-cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2 and Regnase-1, and paracaspase inactivation results in excessive IFNγ production by effector lymphocytes that drives pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity towards destructive autoinflammation.

2014-10-27 | GSE55360 | GEO

Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation

Project description:The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-kB activation, and its proteolytic domain cleaves negative NF-kB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T-cell and innate-like B-cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2 and Regnase-1, and paracaspase inactivation results in excessive IFNÎ³ production by effector lymphocytes that drives pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity towards destructive autoinflammation. Total RNA obtained from T cells with (1h and 4 h) and without stimulation, 3 biological replicates, 3 genotypes (Malt+/-, Malt-/-, MaltPM/-)

2014-10-27 | E-GEOD-55360 | biostudies-arrayexpress

Gene expression profiling of rat jejunum treated with MLT-943, a small molecule MALT1 protease inhibitor

Project description:MALT1 protease inhibition is effective in several preclinical models of autoimmunity and B cell malignancies. However, severe reduction in regulatory T cells (Tregs) and an associated IPEX-like pathology was observed in mice with congenital deficiency of MALT1. Rats treated with MLT-943, a novel potent and selective MALT1 inhibitor showed a rapid and dose-dependent reduction in Tregs and resulted in the progressive appearance of immune abnormalities and clinical signs of an IPEX-like pathology, including severe intestinal inflammation associated with mast cell activation, high serum IgE levels, systemic T cell activation and mononuclear cell infiltration in multiple tissues. Gene expression profiling of rat jejunum was performed to understand the molecular events related to the aforementioned morphological changes. MLT-943 induced a dose-dependent up-regulation of a mast cell, cytotoxic T cells and interferon signatures in rat jejunum. Of note, T cells and IFNγ were described as major drivers of the pathology occurring in MALT1 protease dead animals.

2020-04-30 | E-MTAB-8990 | biostudies-arrayexpress

Gene expression profile at single cell level of CD45+ immune cells from E0771-Vector control tumor tissue, E0771 wildtype Malt1 overexpression tumor tissue and E0771 paracaspase-deficient Malt1 overexpression tumor tissue.

Project description:To invesitigate the additional paracaspase-independent tumor-promoting effect exist for Malt1. We thus collected E0771-Vector control tumor tissue, E0771 wildtype Malt1 (Malt1-WT) overexpression tumor tissue and E0771 paracaspase-deficient Malt1 (Malt1-PD) overexpression tumor tissue, and sorted out immune cells for 10× Genomics single cell RNA-sequencing (scRNA-seq).

2024-04-18 | GSE242554 | GEO

Development of Specific Covalent MALT1 Inhibitors and Biomarkers for B-cell Lymphomas

Project description:The MALT1 paracaspase plays an essential role in Activated B-cell like Diffuse Large B-cell Lymphoma (ABC DLBCL) downstream of B-cell and Toll-like receptor pathway genes mutated in these tumors. Although MALT1 is considered to be a compelling therapeutic target, development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Herein, we developed a target engagement assay that provides a quantitative readout for specific MALT1 inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in a novel class of substrate-mimetic compounds that bind MALT1 active site and, constitute the first pharmacologically tractable irreversible MALT1 inhibitor. We confirmed MALT1 targeting is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that reduction in serum IL10 levels exquisitely correlates with drug PK and degree of MALT1 inhibition in vitro and in vivo and constitutes a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Our new inhibitor revealed insights into the biology of MALT1 in ABC DLBCL, such as driving JAK-STAT signaling and suppressing type I interferon (IFN) response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.

2018-11-14 | GSE108293 | GEO

Malt1 protease is critical in maintaining function of Treg cells and may be a therapeutic target for anti-tumor immunity

Project description:Malt1 protease is critical in maintaining function of Treg cells and may be a therapeutic target for anti-tumor immunity

| PRJNA510753 | ENA

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

Project description:A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.

2012-09-20 | GSE41034 | GEO

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