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A20-mediated negative regulation of canonical NF-κB signaling pathway

  • Immunology & Microbiology in Miami
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Abstract

The nuclear factor kappa B (NF-κB) plays vital role in the immune system by regulating innate and adaptive immunity, development and survival of lymphocytes, and lymphoid organogenesis. All known NF-κB activators converge on the IkappaB kinase (IKK) complex to activate the canonical and non-canonical NF-κB pathways. The IKK complex contains two catalytic subunits (IKKα and IKKβ) and a regulatory subunit NEMO/IKKγ that regulates the canonical NF-κB pathway, whereas IKKα regulates the non-canonical pathway. The process of IKKα activation and its role in the regulation of canonical NF-κB activation remain elusive. The canonical pathway is rapidly activated and produces a potent inflammatory response to bacterial and viral infections as well as different types of stress; however, uncontrolled NF-κB activation can lead to autoimmune diseases and cancers. Therefore, to keep the inflammatory response in check, elaborate negative regulatory mechanisms operate to terminate NF-κB activation at multiple levels by de novo synthesis of NF-κB inhibitory proteins, and orchestration of protein ubiquitination and deubiquitination. The NF-κB target genes, IκBα and A20, play critical roles in termination of the active canonical NF-κB pathway. In this review, we discuss our recent findings describing a novel function for IKKα in nucleating the ubiquitin-editing enzyme A20 complex, a major negative regulator of canonical NF-κB signaling. Consistently with an inhibitory function of IKKα, it is targeted by the human T-cell leukemia virus 1 (HTLV-1) oncoprotein, Tax, to prevent assembly of the A20 complex to maintain persistent NF-κB activation that promotes transformation and survival of virus-transformed cells.

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  1. Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

    Rajeshree Pujari, Richard Hunte, Wasif N. Khan & Noula Shembade

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  1. Rajeshree Pujari
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  2. Richard Hunte
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  4. Noula Shembade
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Correspondence to Noula Shembade.

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Pujari, R., Hunte, R., Khan, W.N. et al. A20-mediated negative regulation of canonical NF-κB signaling pathway. Immunol Res 57, 166–171 (2013). https://doi.org/10.1007/s12026-013-8463-2

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