Regulation of NF-κB by deubiquitinases

The nuclear factor-?B (NF-?B) pathway is a critical regulator of innate and adaptive immunity. Noncanonical K63-linked polyubiquitination plays a key regulatory role in NF-?B signaling pathways by functioning as a scaffold to recruit kinase complexes containing ubiquitin-binding domains. Ubiquitination is balanced by deubiquitinases that cleave polyubiquitin chains and oppose the function of E3 ubiquitin ligases. Deubiquitinases therefore play an important role in the termination of NF-?B signaling and the resolution of inflammation. In this review, we focus on NF-?B regulation by deubiquitinases with an emphasis on A20 and CYLD. Deubiquitinases and the ubiquitin/proteasome components that regulate NF-?B may serve as novel therapeutic targets for inflammatory diseases and cancer.