Regulation of NF-κB signaling by the A20 deubiquitinase

The NF-kappa B transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-kappa B is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the I kappa B kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-kappa B and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas. Cellular & Molecular Immunology (2012) 9, 123-130; doi: 10.1038/cmi.2011.59; published online 20 February 2012