Trends in Immunology
ReviewUbiquitin: tool and target for intracellular NF-κB inhibitors
Section snippets
NF-κB in inflammation: hold your horses
Since its discovery 20 years ago, the transcription factor nuclear factor-κB (NF-κB) has been found to induce a wide variety of genes implicated in the initiation and propagation of the host innate and adaptive immune responses. Upon infection, NF-κB is activated when pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, fungi or parasites are recognized by their cognate toll-like receptors (TLRs) on immune cells. TLR-induced activation of NF-κB leads to the expression of
Ubiquitination in TNF receptor- and TLR–IL-1 receptor-induced signalling to NF-κB activation
NF-κB is a dimeric transcription factor consisting of Rel family members, including NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA/p65, RelB and c-Rel. In resting cells, members of the inhibitor of κB (IκB) protein family, such as IκBα, IκBβ, IκBɛ and the precursors p105 and p100, bind to the NF-κB dimer and thereby impair its translocation to the nucleus. This cytosolic retention of inactive NF-κB is unleashed when the inhibitor of κB kinase (IKK) complex phosphorylates the IκB protein, leading to
Ub-mediated inhibition of NF-κB activation
Two main strategies have evolved that make use of the Ub system to interfere with NF-κB signalling pathways. De-ubiquitinating enzymes (DUBs) that target and disassemble K63 polyubiquitin chains from specific signalling proteins can impair the formation of specific signalling complexes and consequently prevent IKK activation. Alternatively, Ub ligases capable of catalysing K48 polyubiquitination can abrogate NF-κB activation by using Ub as a tool to label plasma-membrane receptors or signalling
Concluding remarks and perspectives
Because of the crucial role of NF-κB in initiating inflammation, the activation of NF-κB is tightly controlled by several endogenous negative regulators that can act at different points along the NF-κB signalling pathway 59, 60. In the past couple of years, tremendous progress has been made in our understanding of the molecular mechanisms of NF-κB activation and the emerging picture positions Ub as a central regulator of NF-κB signalling. Ub not only targets IκB for degradation, but has also
Acknowledgements
K.H. and S.J. are postdoctoral research associates with the Fund for Scientific Research (FWO) – Flanders. Research in our laboratory is supported by grants from the ‘Interuniversitaire Attractiepolen’ (IAP5/12), the FWO (grant 3G010505), and the ‘Geconcerteerde Onderzoeksacties’ (GOA; grant 01G06B6) of Ghent University.
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2015, European Journal of PharmacologyCitation Excerpt :Activation of NF-κB requires phosphorylation and proteolytic degradation of the inhibitory protein IκB-α, an endogenous inhibitors that binds to NF-κB in the cytoplasm (Hayden and Ghosh, 2008). Interfering with the activation of NF-κB could effectively suppress the inflammatory responses in vivo (Schmid and Birbach, 2008; Wullaert et al., 2006). Additionally, the NF-κB pathway has been considered to play a pivotal role in the pathogenesis of lung injury (Wright and Christman, 2003; Zhang and Yue, 2014).
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