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Jens Staal - One of the best experts on this subject based on the ideXlab platform.
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MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging
Frontiers in immunology, 2019Co-Authors: Annelies Demeyer, Jens Staal, Griet Baudelet, Marja Kreike, David Muyllaert, Yasmine Driege, Elien Van Nuffel, Rudi BeyaertAbstract:MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-κB signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans. Genetically engineered mice expressing catalytically inactive MALT1, still exerting its scaffold function, were previously shown to spontaneously develop autoimmunity due to a decrease in Tregs associated with increased effector T cell activation. In contrast, complete absence of MALT1 does not lead to autoimmunity, which has been explained by the impaired effector T cell activation due to the absence of MALT1-mediated signaling. However, here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4.
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MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner.
Frontiers in immunology, 2019Co-Authors: Annelies Demeyer, Jens Staal, Marja Kreike, Yasmine Driege, Ioannis Skordos, Tino Hochepied, Mathijs Baens, Rudi BeyaertAbstract:MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that MALT1 protease-dead knock-in (MALT1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4+ T cells plays a key role in the autoimmune phenotype of MALT1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional MALT1 protease-dead knock-in (MALT1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The MALT1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body MALT1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body MALT1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body MALT1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.
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Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice.
Journal of virology, 2018Co-Authors: E. Kip, Jens Staal, Mathijs Baens, Lynn Verstrepen, H. G. Tima, Marta Romano, Kelly Lemeire, Vanessa Suin, A. Hamouda, Claude LibertAbstract:Rabies virus is a neurovirulent RNA virus, which causes about 59,000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-kappa B signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in MALT1(-/-) compared to MALT1(-/-) mice, and this effect was associated with lower viral load, proinflammatory gene expression, and infiltration and activation of immune cells in the brain. Specific deletion of MALT1 in T cells also delayed disease development, while deletion in myeloid cells, neuronal cells, or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in the case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence and reveal the potential of MALT1 inhibition for therapeutic intervention. IMPORTANCE: Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11-infected mice, providing new insights in the biology of MALT1 and rabies virus infection.
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MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain.
Journal of virology, 2018Co-Authors: E. Kip, Jens Staal, Lynn Verstrepen, H. G. Tima, Sanne Terryn, Marta Romano, Kelly Lemeire, Vanessa Suin, A. Hamouda, Michaël KalaiAbstract:MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1-/- mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1-/- mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1-/- mice at 10 dpi compared to MALT1+/+ infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+ mice. Moreover, MALT1-/- mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.
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02 08 the paracaspase MALT1 plays a central role in the pathogenesis of rheumatoid arthritis
Annals of the Rheumatic Diseases, 2017Co-Authors: Elisabeth Gilis, Jens Staal, Rudi Beyaert, Dirk ElewautAbstract:Background One of the hallmarks of many inflammatory arthritides is their strong linkage with MHC-signalling, which is mirrored by the marked role for adaptive immunity. Accordingly, rheumatoid arthritis (RA) is characterized by the activation of auto-reactive T-cells and the development of auto-antibodies. T-cells may additionally respond to non-TCR mediated signals, which are essential in driving their effector functions. Pathways leading to the modulation of both innate and adaptive signals are therefore of marked interest to study in arthritic diseases. Objectives The paracaspase MALT1 is a key player in the activation and proliferation of immune and non-immune cells. These cells include the lymphoid, myeloid and mast cells, indicating MALT19s crucial role in both innate and adaptive signaling (1). Therefore, MALT1 is regarded a promising target for the treatment of autoimmune diseases and defining its role in the pathogenesis of inflammatory arthritis is a critical first step. Methods To unravel MALT19s role in inflammatory arthritis, we initially assessed MALT1-activation in mice that were challenged with collagen-induced arthritis (CIA), the prototype model for antigen-induced RA. We then addressed the role of MALT1 in the pathogenesis of inflammatory arthritis by challenging MALT1-deficient mice to distinct models of arthritis (CIA and CAIA) or by backcrossing MALT1-deficient mice to TNF DARE mice, representing an SpA-like model. Additionally, CIA was induced in CD4-specific MALT1-deficient mice to determine the importance of MALT1 in T-cells. Results We provide evidence that MALT1 plays a crucial role in the pathogenesis of RA as MALT1-deficent mice were completely protected against CIA. This complete protection was additionally observed in CD4-specific MALT1-deficient mice, indicating that the selective ablation of MALT1 in CD4-positive cells is sufficient for the observed resistance against CIA. CAIA on the other hand, which is a T- and B-cell independent model of RA, did not depend on the presence of MALT1, since both MALT1 +/+ and MALT1 -/- mice showed comparable symptoms of RA. Interestingly, TNF DARE mice that were deficient for MALT1 also showed a reduced enthesitis and ileitis phenotype, although TNF-concentration in the serum of these mice was higher compared to MALT1 +/+ xTNF DARE mice. Conclusions Overall, our data highlight that MALT1 plays a crucial role in the pathogenesis of inflammatory arthritis and represents an interesting candidate to target therapeutically. References Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008; 8 (7): 495–500. Acknowledgements We thank Chris Vercruysse (Department of Basic Medical Sciences, University of Ghent, Belgium) for exerting the three-point-bending tests of the femurs and the lab of Prof. Dr. Luc Van Hoorebeke (Department of Physics and Astronomy) for the use of the μCT-scanner. Disclosure of Interest None declared
Rudi Beyaert - One of the best experts on this subject based on the ideXlab platform.
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MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging
Frontiers in immunology, 2019Co-Authors: Annelies Demeyer, Jens Staal, Griet Baudelet, Marja Kreike, David Muyllaert, Yasmine Driege, Elien Van Nuffel, Rudi BeyaertAbstract:MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-κB signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans. Genetically engineered mice expressing catalytically inactive MALT1, still exerting its scaffold function, were previously shown to spontaneously develop autoimmunity due to a decrease in Tregs associated with increased effector T cell activation. In contrast, complete absence of MALT1 does not lead to autoimmunity, which has been explained by the impaired effector T cell activation due to the absence of MALT1-mediated signaling. However, here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4.
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MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner.
Frontiers in immunology, 2019Co-Authors: Annelies Demeyer, Jens Staal, Marja Kreike, Yasmine Driege, Ioannis Skordos, Tino Hochepied, Mathijs Baens, Rudi BeyaertAbstract:MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that MALT1 protease-dead knock-in (MALT1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4+ T cells plays a key role in the autoimmune phenotype of MALT1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional MALT1 protease-dead knock-in (MALT1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The MALT1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body MALT1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body MALT1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body MALT1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.
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02 08 the paracaspase MALT1 plays a central role in the pathogenesis of rheumatoid arthritis
Annals of the Rheumatic Diseases, 2017Co-Authors: Elisabeth Gilis, Jens Staal, Rudi Beyaert, Dirk ElewautAbstract:Background One of the hallmarks of many inflammatory arthritides is their strong linkage with MHC-signalling, which is mirrored by the marked role for adaptive immunity. Accordingly, rheumatoid arthritis (RA) is characterized by the activation of auto-reactive T-cells and the development of auto-antibodies. T-cells may additionally respond to non-TCR mediated signals, which are essential in driving their effector functions. Pathways leading to the modulation of both innate and adaptive signals are therefore of marked interest to study in arthritic diseases. Objectives The paracaspase MALT1 is a key player in the activation and proliferation of immune and non-immune cells. These cells include the lymphoid, myeloid and mast cells, indicating MALT19s crucial role in both innate and adaptive signaling (1). Therefore, MALT1 is regarded a promising target for the treatment of autoimmune diseases and defining its role in the pathogenesis of inflammatory arthritis is a critical first step. Methods To unravel MALT19s role in inflammatory arthritis, we initially assessed MALT1-activation in mice that were challenged with collagen-induced arthritis (CIA), the prototype model for antigen-induced RA. We then addressed the role of MALT1 in the pathogenesis of inflammatory arthritis by challenging MALT1-deficient mice to distinct models of arthritis (CIA and CAIA) or by backcrossing MALT1-deficient mice to TNF DARE mice, representing an SpA-like model. Additionally, CIA was induced in CD4-specific MALT1-deficient mice to determine the importance of MALT1 in T-cells. Results We provide evidence that MALT1 plays a crucial role in the pathogenesis of RA as MALT1-deficent mice were completely protected against CIA. This complete protection was additionally observed in CD4-specific MALT1-deficient mice, indicating that the selective ablation of MALT1 in CD4-positive cells is sufficient for the observed resistance against CIA. CAIA on the other hand, which is a T- and B-cell independent model of RA, did not depend on the presence of MALT1, since both MALT1 +/+ and MALT1 -/- mice showed comparable symptoms of RA. Interestingly, TNF DARE mice that were deficient for MALT1 also showed a reduced enthesitis and ileitis phenotype, although TNF-concentration in the serum of these mice was higher compared to MALT1 +/+ xTNF DARE mice. Conclusions Overall, our data highlight that MALT1 plays a crucial role in the pathogenesis of inflammatory arthritis and represents an interesting candidate to target therapeutically. References Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008; 8 (7): 495–500. Acknowledgements We thank Chris Vercruysse (Department of Basic Medical Sciences, University of Ghent, Belgium) for exerting the three-point-bending tests of the femurs and the lab of Prof. Dr. Luc Van Hoorebeke (Department of Physics and Astronomy) for the use of the μCT-scanner. Disclosure of Interest None declared
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the paracaspase MALT1 mediates card14 induced signaling in keratinocytes
EMBO Reports, 2016Co-Authors: Inna S Afonina, Jens Staal, Elien Van Nuffel, Griet Baudelet, Marja Kreike, Yasmine Driege, Rudi BeyaertAbstract:Mutations in CARD14 have recently been linked to psoriasis susceptibility. CARD14 is an epidermal regulator of NF‐κB activation. However, the ability of CARD14 to activate other signaling pathways as well as the biochemical mechanisms that mediate and regulate its function remain to be determined. Here, we report that in addition to NF‐κB signaling, CARD14 activates p38 and JNK MAP kinase pathways, all of which are dependent on the paracaspase MALT1. Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis‐associated CARD14 mutations. Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14‐induced cytokine and chemokine expression in human primary keratinocytes. Collectively, our findings demonstrate a novel role for MALT1 in CARD14‐induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis. ![][1] This study shows that the paracaspase MALT1 is indispensable for CARD14‐induced NF‐κB and MAP kinase signaling. Pharmacological inhibition of MALT1 prevents pro‐inflammatory gene expression in primary keratinocytes induced by psoriasis‐associated mutation of CARD14. EMBO Reports (2016) 17: 914–927 [1]: /embed/graphic-1.gif
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The paracaspase MALT1 mediates CARD14‐induced signaling in keratinocytes
EMBO Reports, 2016Co-Authors: Inna S Afonina, Jens Staal, Elien Van Nuffel, Griet Baudelet, Marja Kreike, Yasmine Driege, Rudi BeyaertAbstract:Mutations in CARD14 have recently been linked to psoriasis susceptibility. CARD14 is an epidermal regulator of NF‐κB activation. However, the ability of CARD14 to activate other signaling pathways as well as the biochemical mechanisms that mediate and regulate its function remain to be determined. Here, we report that in addition to NF‐κB signaling, CARD14 activates p38 and JNK MAP kinase pathways, all of which are dependent on the paracaspase MALT1. Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis‐associated CARD14 mutations. Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14‐induced cytokine and chemokine expression in human primary keratinocytes. Collectively, our findings demonstrate a novel role for MALT1 in CARD14‐induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis. ![][1] This study shows that the paracaspase MALT1 is indispensable for CARD14‐induced NF‐κB and MAP kinase signaling. Pharmacological inhibition of MALT1 prevents pro‐inflammatory gene expression in primary keratinocytes induced by psoriasis‐associated mutation of CARD14. EMBO Reports (2016) 17: 914–927 [1]: /embed/graphic-1.gif
Jürgen Ruland - One of the best experts on this subject based on the ideXlab platform.
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The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells
The Journal of clinical investigation, 2012Co-Authors: A Brüstle, Jürgen Ruland, D Brenner, P A Lang, Christiane B. Knobbe, Carl Virtanen, Brian M. Hershenfield, Colin Reardon, Sonja M. Lacher, Pamela S. OhashiAbstract:Effector functions of inflammatory IL-17-producing Th (Th17) cells have been linked to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). However, what determines Th17 cell encephalitogenicity is still unresolved. Here, we show that after EAE induction, mice deficient for the NF-κB regulator MALT1 (MALT1-/- mice) exhibit strong lymphocytic infiltration in the CNS, but do not develop any clinical signs of EAE. Loss of MALT1 interfered with expression of the Th17 effector cytokines IL-17 and GM-CSF both in vitro and in vivo. In line with their impaired GM-CSF secretion, MALT1-/- Th cells failed to recruit myeloid cells to the CNS to sustain neuroinflammation, whereas autoreactive WT Th cells successfully induced EAE in MALT1-/- hosts. In contrast, MALT1 deficiency did not affect Th1 cells. Despite their significantly decreased secretion of Th17 effector cytokines, MALT1-/- Th17 cells showed normal expression of lineage-specific transcription factors. MALT1-/- Th cells failed to cleave RelB, a suppressor of canonical NF-κB, and exhibited altered cellular localization of this protein. Our results indicate that MALT1 is a central, cell-intrinsic factor that determines the encephalitogenic potential of inflammatory Th17 cells in vivo.
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Inhibition of MALT1 Protease Activity Is Selectively Toxic for Activated B CellÃ,–Like Diffuse Large B Cell Lymphoma Cells.
Blood, 2009Co-Authors: Uta Ferch, Andreas Gewies, Michael Düwel, Bernhard Kloo, Daniel Krappmann, Vera Pfaender, Christian Peschel, Jürgen RulandAbstract:Abstract 1271 Poster Board I-293 Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell-like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10 and the paracaspase MALT1 for survival. CARD11, BCL10 and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11/BCL10/MALT1 (CBM) complexes couple upstream events to IKK/NF-κB activation. MALT1 possesses in addition a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here we demonstrate pre-assembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL but not in germinal center B cell-like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment. Disclosures No relevant conflicts of interest to declare.
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Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets
The Journal of experimental medicine, 2009Co-Authors: Michael W. Tusche, Jürgen Ruland, Lesley A. Ward, Doug Mccarthy, Miguel Quintela-fandino, Jennifer L. Gommerman, Tak W. MakAbstract:B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor κB (NF-κB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-κB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-κB2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1−/− marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1−/− MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell–intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
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inhibition of MALT1 protease activity is selectively toxic for activated b cell like diffuse large b cell lymphoma cells
Journal of Experimental Medicine, 2009Co-Authors: Uta Ferch, Andreas Gewies, Michael Düwel, Bernhard Kloo, Daniel Krappmann, Vera Pfänder, Christian Peschel, Jürgen RulandAbstract:Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell–like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11–BCL10–MALT1 (CBM) complexes couple upstream events to IκB kinase (IKK)/NF-κB activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here, we demonstrate preassembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL, but not in germinal center B cell–like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity, and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.
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Inhibition of MALT1 protease activity is selectively toxic for activated B cell–like diffuse large B cell lymphoma cells
Journal of Experimental Medicine, 2009Co-Authors: Uta Ferch, Andreas Gewies, Michael Düwel, Bernhard Kloo, Daniel Krappmann, Vera Pfänder, Christian Peschel, Jürgen RulandAbstract:Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell–like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11–BCL10–MALT1 (CBM) complexes couple upstream events to IκB kinase (IKK)/NF-κB activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here, we demonstrate preassembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL, but not in germinal center B cell–like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity, and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.
Daniel Krappmann - One of the best experts on this subject based on the ideXlab platform.
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MALT1 activation by TRAF6 needs neither BCL10 nor CARD11.
Biochemical and biophysical research communications, 2018Co-Authors: Maureen Bardet, Daniel Krappmann, Thomas Seeholzer, Simone Woods, Adeline Unterreiner, Frédéric BornancinAbstract:The MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) paracaspase couples antigen receptors on lymphocytes to downstream signaling events. Activation of MALT1 is known to involve stimulus-dependent CBM complex formation, that is, the recruitment of BCL10-bound MALT1 to a CARD-Coiled Coil protein. Beyond this canonical, CBM-dependent mechanism of MALT1 activation, recent studies suggest that MALT1 protease activity may be triggered by alternative mechanisms. For instance, the E3-ligase TRAF6 can activate MALT1 proteolytic function and induce MALT1 auto-cleavage. However, the interplay between CBM and TRAF6 with regard to MALT1 activation has remained incompletely elucidated. Here, by generating CRISPR/Cas9-derived knock-out Jurkat T-cells, we show that TRAF6 was dispensable for CARD11/BCL10-dependent MALT1 activation upon T-cell stimulation. However, ectopically-expressed TRAF6 could induce MALT1 activity in Jurkat T-cells devoid of either CARD11 or BCL10. These data provide unequivocal evidence that TRAF6-mediated MALT1 activation does not require the upstream scaffold CARD11 or the interaction between MALT1 and BCL10. Thus, TRAF6 may be part of a previously unidentified non-canonical pathway that triggers MALT1 protease activity independently of canonical CBM signalosomes.
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Molecular architecture and regulation of BCL10-MALT1 filaments
Nature Communications, 2018Co-Authors: Florian Schlauderer, Daniel Krappmann, Thomas Seeholzer, Torben Gehring, Irina Gutsche, Ambroise Desfosses, Mike Strauss, Karl-peter Hopfner, Katja LammensAbstract:The CARD11-BCL10-MALT1 (CBM) complex triggers the adaptive immune response in lymphocytes and lymphoma cells. CARD11/CARMA1 acts as a molecular seed inducing BCL10 filaments, but the integration of MALT1 and the assembly of a functional CBM complex has remained elusive. Using cryo-EM we solved the helical structure of the BCL10-MALT1 filament. The structural model of the filament core solved at 4.9 A resolution identified the interface between the N-terminal MALT1 DD and the BCL10 caspase recruitment domain. The C-terminal MALT1 Ig and paracaspase domains protrude from this core to orchestrate binding of mediators and substrates at the filament periphery. Mutagenesis studies support the importance of the identified BCL10-MALT1 interface for CBM complex assembly, MALT1 protease activation and NF-κB signaling in Jurkat and primary CD4 T-cells. Collectively, we present a model for the assembly and architecture of the CBM signaling complex and how it functions as a signaling hub in T-lymphocytes.
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Development of new MALT1 inhibitors and probes.
Bioorganic & medicinal chemistry, 2016Co-Authors: Bo-tao Xin, Daniel Krappmann, Gisela Schimmack, Bogdan I. Florea, Gijsbert A. Van Der Marel, Christoph Driessen, Herman S. OverkleeftAbstract:Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a promising therapeutic target for the treatment of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Several research groups have reported on the development of MALT1 inhibitors and activity-based probes for in vitro and in situ monitoring and modulating MALT1 activity. In this paper, we report on two activity-based MALT1 probes (6 and 7) and a focused library of 19 new MALT1 inhibitors. Our peptide-based probe 6 labels MALT1 in an activity-based manner. In contrast, probe 7, derived from the known covalent inhibitor MI-2, labels both wild type and catalytically inactive Cys to Ala mutant MALT1, suggesting that MI-2 inhibits MALT1 by reacting with a nucleophilic residue other than the active site cysteine. Furthermore, two of our inhibitors (9, apparent IC50 3.0μM, and 13, apparent IC50 2.1μM) show good inhibitory activity against MALT1 and outperform MI-2 (apparent IC50 7.8μM) in our competitive activity-based protein profiling assay.
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Detection of Recombinant and Cellular MALT1 Paracaspase Activity
Methods of Molecular Biology, 2015Co-Authors: Daniel Nagel, Daniel KrappmannAbstract:MALT1 (mucosa-associated lymphoid tissue protein 1) is a key regulator of antigen-induced NF-κB activation in the adaptive immune response. Activation of proteolytic activity of the MALT1 paracaspase was shown to boost the immune response. Additionally, MALT1 proteolytic activity is essential for the survival of MALT1-dependent lymphoma, such as the activated B-cell type (ABC) of diffuse large B-cell lymphoma (DLBCL) or MALT lymphoma. The functional impact of MALT1 paracaspase on T-cell activation and lymphomagenesis suggests that MALT1 is a promising therapeutic target for the treatment of autoimmune diseases and distinct lymphoma entities. To evaluate the requirement of MALT1 in further detail, direct measurement of its activity status is of great importance. We have established a fluorogenic cleavage assay which can be used to measure activity of recombinant and cellular MALT1. Here we describe the basis of the cleavage assay and include a detailed protocol for recombinant production of MALT1 and also the cellular immunoprecipitation of endogenous MALT1 to determine its proteolytic activity.
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MALT1 protease: equilibrating immunity versus tolerance
The EMBO Journal, 2014Co-Authors: Arianna Bertossi, Daniel KrappmannAbstract:MALT1 paracaspase links signaling cascades emanating from adaptive or innate immune receptors to the canonical NF-κB pathway. Now, Jaworski et al (2014) investigate the physiological role of MALT1 protease activity in mice. Besides the expected requirement of MALT1 activity for immune activation, the study unveils a novel function for MALT1 activity for the development of peripheral tolerance. Thus, MALT1 protease can act immunogenic or tolerogenic, and this interplay will be highly relevant for the clinical development of MALT1 inhibitors.
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MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner.
Frontiers in immunology, 2019Co-Authors: Annelies Demeyer, Jens Staal, Marja Kreike, Yasmine Driege, Ioannis Skordos, Tino Hochepied, Mathijs Baens, Rudi BeyaertAbstract:MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that MALT1 protease-dead knock-in (MALT1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4+ T cells plays a key role in the autoimmune phenotype of MALT1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional MALT1 protease-dead knock-in (MALT1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The MALT1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body MALT1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body MALT1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body MALT1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.
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Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice.
Journal of virology, 2018Co-Authors: E. Kip, Jens Staal, Mathijs Baens, Lynn Verstrepen, H. G. Tima, Marta Romano, Kelly Lemeire, Vanessa Suin, A. Hamouda, Claude LibertAbstract:Rabies virus is a neurovirulent RNA virus, which causes about 59,000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-kappa B signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in MALT1(-/-) compared to MALT1(-/-) mice, and this effect was associated with lower viral load, proinflammatory gene expression, and infiltration and activation of immune cells in the brain. Specific deletion of MALT1 in T cells also delayed disease development, while deletion in myeloid cells, neuronal cells, or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in the case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence and reveal the potential of MALT1 inhibition for therapeutic intervention. IMPORTANCE: Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11-infected mice, providing new insights in the biology of MALT1 and rabies virus infection.
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GRK2 Is a Novel Modulator of the MALT1 Oncoprotein
Blood, 2016Co-Authors: Jing Cheng, Margot Thome, Mathijs Baens, Ming Zhang, Heejae Kang, Narayanan Parameswaran, Phillip C. Delekta, Nathaniel E Hubel, Vincent J. Concel, Peter C LucasAbstract:Background and Significance: Lymphocyte antigen receptor-dependent stimulation of the NF-κB transcription factor is a key event during the normal adaptive immune response. However, dysregulated activation of these signaling pathways can lead to lymphoma. Stimulation of the B-or T-cell receptor promotes assembly of the CARMA1-Bcl10-MALT1 (CBM) signaling complex, where MALT1 functions as the essential effector molecule by carrying out two important functions: First, as a scaffold to recruit and activate components of the canonical NF-κB signaling machinery, and second, acts as a protease to enzymatically cleave and inactivate multiple substrates including several negative regulators of canonical NF-κB signaling. Activating mutations in either BCR or CARMA1 promote constitutive and exaggerated MALT1 activity and are seen as driver mutations in diffuse large B cell lymphoma (DLBCL). Aberrant MALT1 activity also underlies the pathogenesis of MALT lymphoma, another subtype of B-cell malignancy. As such, MALT1 has emerged as a potential new target for pharmaceutical inhibition in the treatment of lymphoma. Here, we describe our discovery of a novel MALT1-binding partner, G protein-coupled receptor kinase 2 (GRK2). We hypothesize that GRK2 plays a critical role in the pathogenesis of lymphoma by modulating MALT1 activity. Methods and Results: Using co-immunoprecipitation and liquid chromatography mass spectrometry we identified GRK2 as a novel MALT1-interacting protein. We validated our results by showing that endogenous GRK2 and MALT1 co-immunoprecipitate (CO-IP) in both B cells and T cells. We next utilized GST-tagged purified proteins to demonstrate a direct interaction between GRK2 and MALT1. We then performed a number of studies to investigate the functional consequences of GRK2 interaction with MALT1. A CO-IP assay demonstrated that GRK2 inhibits Bcl10-dependent binding to MALT1, and a luciferase reporter assay revealed that GRK2 inhibits Bcl10/MALT1-dependent NF-κB activity. In addition, we demonstrated that GRK2 also inhibits MALT1 proteolytic activity using Western blot analysis of two known MALT1 substrates, the deubiquitinase cylindromatosis (CYLD) and the NF-kB family member RelB. Moreover, in Jurkat T cells, overexpression of GRK2 impeded AgR-induced NF-κB activation while stable GRK2 knockdown resulted in enhanced AgR-induced phosphorylation of inhibitor of kappaB (IκB) and secretion of interleukin2 (IL-2). We next began to investigate the potential of GRK2 to function as a tumor suppressor by blocking MALT1 activity. Of note, utilizing a published data set to compare GRK2 mRNA expression in 44 DLBCL patient samples to that of 20 samples of healthy B-cell controls, we found that GRK2 mRNA levels are markedly lower in DLBCL cases. We also compared GRK2 mRNA levels among patients diagnosed with DLBCL grouped by vital status, using data from the Cancer Genome Atlas (TCGA). We found that tumors from patients who died of disease within three years expressed significantly lower levels of GRK2 as compared to tumors from patients alive after three years. We also wished to investigate the impact of GRK2 expression on activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL) cells, which require MALT1 activity for growth and survival. We were successful in engineering GRK2 overexpression in control germinal center B-cell like (GCB) DLBCL cells, which do not depend on MALT1 activity for growth. In contrast, we found that in ABC-DLBCL cells, which do depend on MALT1 activity, GRK2 overexpression greatly impairs cell proliferation, making it difficult to grow these engineered cells. These data provide support for the concept that GRK2 may have a potential tumor suppressor role in MALT1-dependent lymphoma. Conclusions: Our study represents the first report of a negative modulator of MALT1 and provides critical new insight into mechanisms regulating its activity. We hope to harness this information in developing novel strategies for inhibiting MALT1-dependent lymphomagenesis. Disclosures No relevant conflicts of interest to declare.
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MALT1 Auto-Proteolysis Is Essential for NF-κB-Dependent Gene Transcription in Activated Lymphocytes
PloS one, 2014Co-Authors: Mathijs Baens, Margot Thome, Luca Bonsignore, Riet Somers, Charlotte Vanderheydt, Stephen D. Weeks, Jenny Gunnarsson, Ewa Nilsson, Robert G. Roth, Peter MarynenAbstract:Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor–mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.
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The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling.
Oncogene, 2013Co-Authors: Shaun Rosebeck, Mathijs Baens, Aasia O. Rehman, Ingrid J. Apel, Dawn Kohrt, Alex Appert, Marie Anne O’donnell, Adrian T. Ting, Peter C LucasAbstract:The API2-MALT1 fusion oncoprotein is created by the recurrent t(11;18)(q21;q21) chromosomal translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. We identified receptor interacting protein-1 (RIP1) as a novel API2-MALT1-associated protein, and demonstrate that RIP1 is required for API2-MALT1 to stimulate canonical nuclear factor kappa B (NF-κB). API2-MALT1 promotes ubiquitination of RIP1 at lysine (K) 377, which is necessary for full NF-κB activation. Furthermore, we found that TNF receptor-associated factor 2 (TRAF2) recruitment is required for API2-MALT1 to induce RIP1 ubiquitination, NF-κB activation and cellular transformation. Although both TRAF2 and RIP1 interact with the API2 moiety of API2-MALT1, this moiety alone is insufficient to induce RIP1 ubiquitination or activate NF-κB, indicating that API2-MALT1-dependent RIP1 ubiquitination represents a gain of function requiring the concerted actions of both the API2 and MALT1 moieties of the fusion. Intriguingly, constitutive RIP1 ubiquitination was recently demonstrated in several solid tumors, and now our study implicates RIP1 ubiquitination as a critical component of API2-MALT1-dependent lymphomagenesis.