The non-canonical IκB kinases IKKε and TBK1 as potential targets for the development of novel therapeutic drugs.
ABSTRACT IκB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are two non-canonical IKKs which are involved in interferon regulatory factor (IRF) as well as nuclear factor kappaB (NF-κB) signaling cascades. Both kinases have already been linked to the pathophysiology of several diseases and therefore been suggested as potential promising targets for the development of therapeutic drugs. In this review, we summarize the roles of IKKε and TBK1 in different diseases and outline therapeutic options for modulation of these kinases.
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ABSTRACT: The RhoGTPases, with RhoA, Cdc42 and Rac being major members, are a group of key ubiquitous proteins present in all eukaryotic organisms that subserve such important functions as cell migration, adhesion and differentiation. The nuclear factor kappa (NFκB) is a family of constitutive and inducible transcription factors that through their diverse target genes, play a major roles in processes such as cytokine expression, stress regulation, cell division and transformation. Research over this decade has uncovered new molecular links between the RhoGTPases and the NFκB pathway, with the RhoGTPases playing a positive or negative regulatory role on NFκB activation depending on the context. The RhoA-NFκB has been shown to be important in cytokine activated NFκB processes, such as those induced by TNFα. On the other hand, Rac is important for activating the NFκB response downstream of integrin activation, such as after phagocytosis. Specific residues of Rac1 are important for triggering NFκB activation, and mutations do obliterate this response. Other upstream triggers of the RhoGTPase NFκB interactions include the p120 catenin, with implications for skin inflammation. The networks described here are not only important areas for further research, but are also significant for discovery of targets for translational medicine.Bioscience Reports 05/2014; · 1.88 Impact Factor
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ABSTRACT: TANK-binding kinase 1 (TBK1) plays pivotal roles in antiviral innate immunity. TBK1 mediates the activation of interferon regulatory factor (IRF) 3, leading to the induction of type I IFNs (IFN-α/β) following viral infections. TBK1 must be tightly regulated to effectively control viral infections and maintain immune homeostasis. TBK1 activity can be regulated in a variety of ways, such as phosphorylation, ubiquitination, kinase activity modulation and prevention of functional TBK1-containing complexes formation. Furthermore, multiple viruses have evolved elaborate strategies to circumvent IFN responses by targeting TBK1. Here we provide an overview of TBK1 in antiviral immunity and recent developments on the regulation of TBK1 activity.FEBS letters 02/2013; · 3.54 Impact Factor
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ABSTRACT: Nuclear factor (NF)-κB transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-κB signaling contribute to the pathogenesis of immunological disorders. NF-κB is a well-known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-κB plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-κB may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-κB signaling. This review focuses on recent progress regarding NF-κB regulation and its association with autoimmunity.Trends in Immunology 02/2013; · 9.49 Impact Factor