Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA239410 | ENA |
REPOSITORIES: ENA
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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
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. 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
Project description: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.
2018-12-20 | GSE124089 | GEO
Project description:Uncoupling protein 1 (UCP1) is thought to be a major regulator of whole-body energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss of function model has recently been shown to have destructive effects on the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as an allosteric site on UCP1 that elevates protein activity upon covalent modification. Here we examine the physiological importance of this site through the generation of a UCP1 cysteine-253 null mouse (UCP1 C253A), the first genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, instead we find that lack of cysteine-253 results in substantial immune cell infiltration and inflammatory pathology in adipose tissues of male, but not female mice. Together, our results establish the UCP1 cysteine-253 activation site as a regulator of acute thermogenesis and sex-dependent adipose tissue inflammation.
2021-12-15 | PXD029270 | Pride
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
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
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. HBL-1 cells (n=8) were treated with IkB kinase beta inhibitor MLN120B (25 micromolar; Calbiochem) for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3). HBL-1 cells (n=4) and OCI-Ly3 cells (n=4) were treated with MALT1 inhibitor z-VRPR-fmk (50 micromolar; Alexis Biochemicals) for 6h, 12h, 24h, and 30h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3).
2012-09-20 | E-GEOD-41034 | biostudies-arrayexpress
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.
2015-10-24 | GSE74297 | GEO
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
Project description:Regulatory T (Treg) cells are crucial for maintaining peripheral immune tolerance and preventing destructive autoreactive responses, but how heterogeneous Treg populations establish tolerant status remains unclear. Here, we found that Zinc finger protein 335 (Zfp335) is indispensable for the differentiation and maintenance of effector Treg (eTreg) population and immunological self-tolerance in neonates.Mice with Zfp335 deletion in Treg cells exhibit early-onset autoimmune disease with severe inflammation in multiple organs and unrestricted activation and expansion of conventional T cells.
2022-05-01 | GSE189041 | GEO