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BCL10GFP fusion protein as a substrate for analysis of determinants required for Mucosa-Associated Lymphoid Tissue 1 (MALT1)-mediated cleavage  [cached]
Jou Shin-Yi,Chang Chien-Chih,Wu Chun-Hsien,Chen Mei-Ru
Journal of Biomedical Science , 2012, DOI: 10.1186/1423-0127-19-85
Abstract: Background MALT1 belongs to a family of paracaspase and modulates NF-κB signaling pathways through its scaffolding function and proteolytic activity. MALT1 cleaves protein substrates after a positively charged Arginine residue. BCL10, a 233 amino acids polypeptide, is identified as one of the MALT1 proteolytic substrates. MALT1 cleaves BCL10 at the C-terminal end of Arg228. A mere 5 amino acids difference between the substrate and the proteolytic product made it difficult to tell whether the cleavage event took place by using a simple western blot analysis. Here, BCL10GFP was constructed and utilized to examine the specificity and domain determinants for MALT1 cleavage in cells. Methods Various BCL10GFP constructs were transfected into HEK293T cell with MALT1 construct by using calcium phosphate-DNA precipitation method. Lysates of transfectants were resolved by SDS/PAGE and analyzed by western blot analysis. Results BCL10GFP was proteolytically processed by MALT1 as BCL10. The integrity of caspase recruitment domain (CARD) and MALT1-interacting domain on BCL10 were required for MALT1 proteolytic activity. Besides the invariant P1 cleavage site Arg228, P4 Leu225 played a role in defining BCL10 as a good substrate for MALT1. Conclusions We offered a way of monitoring the catalytic activity of MALT1 in HEK293T cells using BCL10GFP as a substrate. BCL10GFP can be utilized as a convenient tool for studying the determinants for efficient MALT1 cleavage in HEK293T cells
Structural Insights into the Assembly of CARMA1 and BCL10  [PDF]
Siwei Li, Xue Yang, Juan Shao, Yuequan Shen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042775
Abstract: The CBM complex (CARMA1, BCL10 and MALT1) plays a crucial role in B and T lymphocyte activation. CARMA1 serves as a scaffold for BCL10, MALT1 and other effector proteins and regulates various signaling pathways related to the immune response. The assembly of CARMA1 and BCL10 is mediated through a CARD-CARD interaction. Here, we report the crystal structure of the CARD domain of CARMA1 at a resolution of 1.75 ?. The structure consists of six helices, as previously determined for CARD domains. Structural and computational analysis identified the binding interface between CARMA1-CARD and BCL10-CARD, which consists of a basic patch in CARMA1 and an acidic patch in BCL10. Site-directed mutagenesis, co-immunoprecipitation and an NF-κB activation assay confirmed that the interface is necessary for association and downstream signaling. Our studies provide molecular insight into the assembly of CARMA1 and BCL10.
Functional Characterization of Porcine (Sus scrofa) BCL10  [PDF]
Pellegrino Mazzone, Ivan Scudiero, Angela Ferravante, Marina Paolucci, Luca E. D’Andrea, Ettore Varricchio, Gianluca Telesio, Maddalena Pizzulo, Tiziana Zotti, Carla Reale, Pasquale Vito, Romania Stilo
Open Journal of Immunology (OJI) , 2015, DOI: 10.4236/oji.2015.52007
Abstract: Human BCL10 (hBCL10) protein is a signal transduction molecule originally identified because of its direct involvement in a subset of mucosa-associated lymphoid tissue (MALT) lymphomas, and later recognized as a crucial factor in regulating activation of NF-kB transcription factor following antigen receptor stimulation on lymphocytes. In this study, we characterized the NF-kB inducing activity of porcine BCL10 (pBCL10). pBCL10 oligimerizes, binds to components of the CARMA/ BCL10/MALT1 complex and forms cytoplasmic filaments. Functionally, in human cells pBCL10 is more effective in activating NF-kB compared to hBCL10, possibly due to the lack of carboxy-terminal inhibitory serine residues present in the human protein. Also, depletion experiments carried out through expression of short hairpin RNAs targeting hBCL10 indicate that pBcl10 can functionally replace the human protein and retains its higher NF-kB-inducing property in the absence of hBCL10. Our results contribute useful information on BCL10 protein in pigs, and may help the development of strategies based on the control of the immune response in pigs.
B cell antigen receptor-induced activation of an IRAK4-dependent signaling pathway revealed by a MALT1-IRAK4 double knockout mouse model
Almut Dufner, Wolfgang W Schamel
Cell Communication and Signaling , 2011, DOI: 10.1186/1478-811x-9-6
Abstract: Using genetic and biochemical approaches, we demonstrate that the IRAK4- and IRAK1-dependent TLR signaling branch is activated upon BCR triggering to induce partial NF-κB activation. BCR-induced MALT1-independent IκB degradation and B cell proliferation were inhibited in MALT1/IRAK4 double knockout B cells. Moreover, IRAK1 was recruited into lipid rafts upon BCR stimulation and activated following transient recruitment of IRAK4.We propose that the observed crosstalk between BCR and TLR signaling components may contribute to the discrimination of signals that emanate from single and dual receptor engagement to control adaptive B cell responses.Activation and survival of B cells in response to antigen receptor (AgR) engagement depends on the activation of the inducible transcription factor NF-κB. BCR-induced NF-κB activation is mediated by components of the so-called CBM signaling complex. The CBM complex consists of the CARD-containing membrane-associated guanylate kinase CARD11, the CARD-containing adaptor protein BCL10, and the death domain (DD)-containing "paracaspase" MALT1 [1-5]. Complex assembly and the recruitment of downstream effectors are triggered by a receptor-proximal tyrosine phosphorylation cascade that leads to the activation of protein kinase C-β (PKC-β) [6,7]. PKC-β phosphorylates a linker region in the adaptor molecule CARD11, which enables CARD11 to recruit BCL10 and MALT1 into lipid rafts [8]. BCL10 and MALT1 then mediate activation of the IKK complex that induces degradation of IκB proteins, the inhibitors of NF-κB that retain it in the cytoplasm, which ultimately leads to the activation of NF-κB [9]. This process requires lysine 63-linked polyubiquitination events that involve the E3-ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) and mediate complex formation between components of the CBM complex, TRAF6, transforming growth factor β-activated kinase 1 (TAK1) and the IKK complex [10-13].Paradoxical to the established requireme
Monoubiquitination and Activity of the Paracaspase MALT1 Requires Glutamate 549 in the Dimerization Interface  [PDF]
Katrin Cabalzar, Christiane Pelzer, Annette Wolf, Georg Lenz, Justyna Iwaszkiewicz, Vincent Zoete, Stephan Hailfinger, Margot Thome
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072051
Abstract: The mucosa-associated lymphoid tissue protein-1 (MALT1, also known as paracaspase) is a protease whose activity is essential for the activation of lymphocytes and the growth of cells derived from human diffuse large B-cell lymphomas of the activated B-cell subtype (ABC DLBCL). Crystallographic approaches have shown that MALT1 can form dimers via its protease domain, but why dimerization is relevant for the biological activity of MALT1 remains largely unknown. Using a molecular modeling approach, we predicted Glu 549 (E549) to be localized within the MALT1 dimer interface and thus potentially relevant. Experimental mutation of this residue into alanine (E549A) led to a complete impairment of MALT1 proteolytic activity. This correlated with an impaired capacity of the mutant to form dimers of the protease domain in vitro, and a reduced capacity to promote NF-κB activation and transcription of the growth-promoting cytokine interleukin-2 in antigen receptor-stimulated lymphocytes. Moreover, this mutant could not rescue the growth of ABC DLBCL cell lines upon MALT1 silencing. Interestingly, the MALT1 mutant E549A was unable to undergo monoubiquitination, which we identified previously as a critical step in MALT1 activation. Collectively, these findings suggest a model in which E549 at the dimerization interface is required for the formation of the enzymatically active, monoubiquitinated form of MALT1.
Oligomeric Structure of the MALT1 Tandem Ig-Like Domains  [PDF]
Liyan Qiu, Sirano Dhe-Paganon
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023220
Abstract: Background Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling. Principal Findings Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 ?2 and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization. Conclusions The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
MALT1-?A20?-?NF-κB?信号分子在MM中的表达特点  [PDF]
王 旭,徐 玲,张 帆,徐 艳,吴秀丽,杨力建,陈少华,,,卢育洪,李扬秋
暨南大学学报(自然科学与医学版) , 2013, DOI: R733;Q786
Abstract: 目的了解多发性骨髓瘤(MM)患者外周血中黏膜相关组织淋巴瘤异位基因1(MALT1)、A20与核转录因子κB(NF-κB)基因的表达特点。方法采用SYBRGreenⅠ荧光实时定量PCR和相对定量分析法检测20例MM患者(Ⅰ期7例,Ⅱ期3例,Ⅲ期10例)及21例健康人外周血单个核细胞(PBMC)中MALT1、A20和NF-κB基因的表达情况。以β2微球蛋白基因(β2m)作为内参;采用相对定量公式α-ΔCt×100%,分别计算MALT1、A20和NF-κB基因的表达水平。结果MM患者PBMC中的MALT1和A20基因的表达水平较健康人都有明显的降低(P=0.000),而MM中NF-κB基因的表达水平较正常人有所升高,但无统计学差异(P>0.05)。在健康人组,MALT1和NF-κB的表达水平呈现正相关(p=0.001,r=0.666),而在MM组,MALT1、A20与NF-κB3种基因均不存在明显相关性。同时,Ⅰ、Ⅱ、Ⅲ期MM患者MALT1基因的表达量较健康人明显降低(p<0.05),A20基因的表达量较健康人明显降低(p<0.01),而Ⅰ、Ⅱ、Ⅲ期MM患者MALT1、A20和NF-κB之间的表达情况均无统计学差异。结论当MALT1-A20介导的细胞免疫和炎症的信号通路发生异常改变时,可能与MM的发生发展有着密切关系。
T(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the V gene mutation status  [cached]
Xavier Sagaert,Brigitte Maes,Vera Vanhentenrijk,Mathijs Baens
World Journal of Gastrointestinal Oncology , 2011,
Abstract: AIM: To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker CD27.METHODS: The VH gene of 7 t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas was amplified by PCR using family specific VH primers and a consensus JH primer. PCR products were sequenced and mutation analysis of the CDR and the FR regions was performed. All cases were immunostained for CD27.RESULTS: One case showed unmutated VH genes while the others showed mutated VH genes with mutation frequencies ranging from 1.3 to 14.7% and with evidence of antigen selection in 2 cases. These data suggest that the translocation t(11;18)(q21;q21) can target either B-cells at different stages of differentiation or naive B-cells that retain the capacity to differentiate upon antigen stimulation. All cases but one displayed weak to strong CD27 expression which did not correlate with the VH gene mutation status.CONCLUSION: t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the VH mutation status and CD27 is not a marker of somatically mutated B-cells.
Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: A Colombian perspective  [cached]
Sally Yepes,Maria Mercedes Torres,Carlos Saavedra,Rafael Andrade
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i7.685
Abstract: AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia. METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication. RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells. CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases.
Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2  [PDF]
Sonja I. Gringhuis ,Brigitte A. Wevers,Tanja M. Kaptein,Toni M. M. van Capel,Bart Theelen,Teun Boekhout,Esther C. de Jong,Teunis B. H. Geijtenbeek
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1001259
Abstract: C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel.
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