Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Cell Mol Immunol. 2012 Mar;9(2):123-30. doi: 10.1038/cmi.2011.59. Epub 2012 Feb 20.
The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-κB is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IκB 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-κB 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.
NF-κB 转录因子是炎症和先天免疫信号通路的核心介质。NF-κB 的激活是通过关键信号分子的 K63 连接多泛素化实现的，该多泛素化招募激酶复合物，激酶复合物又激活 IκB 激酶 (IKK)。泛素化是一个高度动态的过程，由去泛素化酶平衡，这些酶可以切割多泛素链并终止下游信号事件。A20 去泛素酶是 NF-κB 和炎症的关键负调节剂，因为 A20 缺陷小鼠会发展为不受控制和自发的多器官炎症。此外，A20 基因座的特定多态性使人类易患自身免疫性疾病。最近的研究还表明，A20 是一种重要的肿瘤抑制因子，在 B 细胞淋巴瘤中失活。因此，针对 A20 可能成为自身免疫性疾病和淋巴瘤新疗法的基础。
