A20-mediated negative regulation of canonical NF-kappa B signaling pathway

作者：Pujari Rajeshree; Hunte Richard; Khan Wasif N; Shembade Noula^*

来源：Immunologic Research, 2013, 57(1-3): 166-171.

DOI：10.1007/s12026-013-8463-2

• Ubiquitin NF-kappa B
• IKK
• Innate immunity
• Autoimmunity

The nuclear factor kappa B (NF-kappa B) plays vital role in the immune system by regulating innate and adaptive immunity, development and survival of lymphocytes, and lymphoid organogenesis. All known NF-kappa B activators converge on the IkappaB kinase (IKK) complex to activate the canonical and non-canonical NF-kappa B pathways. The IKK complex contains two catalytic subunits (IKK alpha and IKK beta) and a regulatory subunit NEMO/IKK gamma that regulates the canonical NF-kappa B pathway, whereas IKK alpha regulates the non-canonical pathway. The process of IKK alpha activation and its role in the regulation of canonical NF-kappa B 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-kappa B activation can lead to autoimmune diseases and cancers. Therefore, to keep the inflammatory response in check, elaborate negative regulatory mechanisms operate to terminate NF-kappa B activation at multiple levels by de novo synthesis of NF-kappa B inhibitory proteins, and orchestration of protein ubiquitination and deubiquitination. The NF-kappa B target genes, I kappa B alpha and A20, play critical roles in termination of the active canonical NF-kappa B pathway. In this review, we discuss our recent findings describing a novel function for IKK alpha in nucleating the ubiquitin-editing enzyme A20 complex, a major negative regulator of canonical NF-kappa B signaling. Consistently with an inhibitory function of IKK alpha, 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-kappa B activation that promotes transformation and survival of virus-transformed cells.

• 出版日期2013-12