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Mc Guire C.,Unit of Molecular Signal Transduction in Inflammation | Mc Guire C.,Ghent University | Prinz M.,Albert Ludwigs University of Freiburg | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | And 3 more authors.
Trends in Molecular Medicine | Year: 2013

The nuclear factor kappa B (NF-κB) signaling cascade plays a critical role in the regulation of immune and inflammatory responses and has been implicated in the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the main animal model of MS. NF-κB is essential for peripheral immune cell activation and the induction of pathology, but also plays crucial roles in resident cells of the central nervous system (CNS) during disease development. Here we review recent evidence clarifying the role of NF-κB in the different cell compartments contributing to MS pathology and its implications for the development of therapeutic strategies for the treatment of MS and other demyelinating pathologies of the CNS. © 2013 Elsevier Ltd.


Verhelst K.,Unit of Molecular Signal Transduction in Inflammation | Verhelst K.,Ghent University | Carpentier I.,Unit of Molecular Signal Transduction in Inflammation | Carpentier I.,Ghent University | And 2 more authors.
Cytokine and Growth Factor Reviews | Year: 2011

TNF is a multifunctional cytokine that plays a key role in innate immunity by inducing the expression of a variety of genes that are involved in an inflammatory response. TNF-induced NF-κB activation is one of the best studied signaling pathways in mammalian cells and has recently led to a revival of research in the biology of ubiquitin. Many NF-κB signaling proteins are modified by specific ubiquitin ligases with different types of ubiquitin chains that are recognized by other proteins and which determine the outcome of ubiquitination. In addition, specific de-ubiquitinases make the whole process reversible. This review summarizes recent findings that have shaped our current understanding on the role of cytoplasmic ubiquitination events in the regulation of TNF-induced NF-κB signaling. © 2011 Elsevier Ltd.


Maelfait J.,Unit of Molecular Signal Transduction in Inflammation
PLoS pathogens | Year: 2012

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.


Verhelst K.,Unit of Molecular Signal Transduction in Inflammation | Verhelst K.,Ghent University | Carpentier I.,Unit of Molecular Signal Transduction in Inflammation | Carpentier I.,Ghent University | And 10 more authors.
EMBO Journal | Year: 2012

Linear polyubiquitination of proteins has recently been implicated in NF-κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced NF-κB activation via its C-terminal zinc-finger 7 (ZF7) domain. Expression of a polypeptide corresponding to only ZF7 was sufficient to inhibit TNF-induced NF-κB activation. Both A20 and ZF7 can form a complex with NEMO and LUBAC, and are able to prevent the TNF-induced binding of NEMO to LUBAC. Finally, we show that ZF7 preferentially binds linear polyubiquitin chains in vitro, indicating A20-ZF7 as a novel linear ubiquitin-binding domain (LUBID). We thus propose a model in which A20 inhibits TNF- and LUBAC-induced NF-κB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF-induced interaction between LUBAC and NEMO. © 2012 European Molecular Biology Organization | All Rights Reserved.


Maelfait J.,Unit of Molecular Signal Transduction in Inflammation | Maelfait J.,Ghent University | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | Beyaert R.,Ghent University
Microbiology and Molecular Biology Reviews | Year: 2012

Detection of viruses by the innate immune system involves the action of specialized pattern recognition receptors. Intracellular RIG-I receptors sense the presence of viral nucleic acids in infected cells and trigger signaling pathways that lead to the production of proinflammatory and antiviral proteins. Over the past few years, posttranslational modification of RIG-I and downstream signaling proteins by different types of ubiquitination has been found to be a key event in the regulation of RIG-I-induced NF-κB and interferon regulatory factor 3 (IRF3) activation. Multiple ubiquitin ligases, deubiquitinases, and ubiquitin binding scaffold proteins contribute to both positive and negative regulation of the RIG-I-induced antiviral immune response. A better understanding of the function and activity of these proteins might eventually lead to the development of novel therapeutic approaches for management of viral diseases. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Matmati M.,Unit of Molecular Signal Transduction in Inflammation | Matmati M.,Ghent University | Jacques P.,Ghent University | Maelfait J.,Unit of Molecular Signal Transduction in Inflammation | And 25 more authors.
Nature Genetics | Year: 2011

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-°B signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-°B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies. © 2011 Nature America, Inc. All rights reserved.


Vereecke L.,Unit of Molecular Signal Transduction in Inflammation | Vereecke L.,Ghent University | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | Beyaert R.,Ghent University | And 2 more authors.
Biochemical Society Transactions | Year: 2011

A20 [also known as TNFAIP3 (tumour necrosis factor α-induced protein 3)] restricts and terminates inflammatory responses through modulation of the ubiquitination status of central components in NF-κB (nuclear factor κB), IRF3 (interferon regulatory factor 3) and apoptosis signalling cascades. The phenotype of mice with full or conditional A20 deletion illustrates that A20 expression is essential to prevent chronic inflammation and autoimmune pathology. In addition, polymorphisms within the A20 genomic locus have been associated with multiple inflammatory and autoimmune disorders, including SLE (systemic lupus erythaematosis), RA (rheumatoid arthritis), Crohn's disease and psoriasis. A20 has also been implicated as a tumour suppressor in several subsets of B-cell lymphomas. The present review outlines recent findings that illustrate the effect of A20 defects in disease pathogenesis and summarizes the identified A20 polymorphisms associated with different immunopathologies. ©The Authors Journal compilation ©2011 Biochemical Society.


Verstrepen L.,Unit of Molecular Signal Transduction in Inflammation | Verstrepen L.,Ghent University | Verhelst K.,Unit of Molecular Signal Transduction in Inflammation | Verhelst K.,Ghent University | And 7 more authors.
Biochemical Pharmacology | Year: 2010

A20 (also known as TNFAIP3) is a cytoplasmic protein that plays a key role in the negative regulation of inflammation and immunity. Polymorphisms in the A20 gene locus have been identified as risk alleles for multiple human autoimmune diseases, and A20 has also been proposed to function as a tumor suppressor in several human B-cell lymphomas. A20 expression is strongly induced by multiple stimuli, including the proinflammatory cytokines TNF and IL-1, and microbial products that trigger pathogen recognition receptors, such as Toll-like receptors. A20 functions in a negative feedback loop, which mediates its inhibitory functions by downregulating key proinflammatory signaling pathways, including those controlling NF-κB- and IRF3-dependent gene expression. Activation of these transcription factors is controlled by both K48- and K63- polyubiquitination of upstream signaling proteins, respectively triggering proteasome-mediated degradation or interaction with other signaling proteins. A20 turns off NF-κB and IRF3 activation by modulating both types of ubiquitination. Induction of K48-polyubiquitination by A20 involves its C-terminal zinc-finger ubiquitin-binding domain, which may promote interaction with E3 ligases, such as Itch and RNF11 that are involved in mediating A20 inhibitory functions. A20 is thought to promote de-ubiquitination of K63-polyubiquitin chains either directly, due to its N-terminal deubiquitinase domain, or by disrupting the interaction between E3 and E2 enzymes that catalyze K63-polyubiquitination. A20 is subject to different mechanisms of regulation, including phosphorylation, proteolytic processing, and association with ubiquitin binding proteins. Here we review the expression and biological activities of A20, as well as the underlying molecular mechanisms. © 2010 Elsevier Inc.


van Loo G.,Unit of Molecular Signal Transduction in Inflammation | van Loo G.,Ghent University | Beyaert R.,Unit of Molecular Signal Transduction in Inflammation | Beyaert R.,Ghent University
Arthritis Research and Therapy | Year: 2011

The transcription factor NF-κB plays crucial roles in the regulation of inflammation and mmune responses, and inappropriate NF-κB activity has been linked with many autoimmune and inflammatory diseases, including rheumatoid arthritis. Cells employ a multilayered control system to keep NF-κB signalling in check, including a repertoire of negative feedback regulators ensuring termination of NF-κB responses. Here we will review various negative regulatory mechanisms that have evolved to control NF-κB signalling and which have been implicated in the pathogenesis of rheumatoid arthritis. © 2011 BioMed Central Ltd.


Verhelst K.,Unit of Molecular Signal Transduction in Inflammation | Verhelst K.,Ghent University | Verstrepen L.,Unit of Molecular Signal Transduction in Inflammation | Verstrepen L.,Ghent University | And 4 more authors.
Biochemical Pharmacology | Year: 2013

The innate immune system forms our first line of defense against invading pathogens and relies for a major part on the activation of two transcription factors, NF-κB and IRF3. Signaling pathways that activate these transcription factors are intertwined at the level of the canonical IκB kinases (IKKα, IKKβ) and non-canonical IKK-related kinases (IKKε, TBK1). Recently, significant progress has been made in understanding the function and mechanism of action of IKKε in immune signaling. In addition, IKKε impacts on cell proliferation and transformation, and is thereby also classified as an oncogene. Studies with IKKε knockout mice have illustrated a key role for IKKε in inflammatory and metabolic diseases. In this review we will highlight the mechanisms by which IKKε impacts on signaling pathways involved in disease development and discuss its potential as a novel therapeutic target. © 2013 Elsevier Inc.

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