Ubiquitination-mediated NF-κB regulation in inflammatory response

Abstract

Nuclear factor (NF)-κB is a central signaling pathway regulating inflammatory, adaptive, and innate immune responses, and impaired NF-κB activity is implicated in multiple disorders, including cancer, autoimmune, inflammatory, and neurodegenerative diseases, and metabolic syndrome. Lys63 (K63)- and K48- linked polyubiquitin chains, catalyzed by specific ubiquitin ligases (E3s) such as TNF receptor-associated factor (TRAF), inhibitor of apoptosis (IAP), and β-TrCP, are involved in the NF-κB pathway. In addition, we found a ubiquitin ligase complex named LUBAC (linear ubiquitin chain assembly complex), composed of HOIL-1L, HOIP, and SHARPIN. LUBAC generates a novel type of Met1 (M1)- linked linear polyubiquitin chain, which serves as a scaffold to recruit I?B kinase (IKK), and then activates IKK auto-catalytically by trans -phosphorylation. Genetic ablation and polymorphism of LUBAC subunits induces multiple disorders, including dermatitis, autoinflammation, immunodeficiency, and B-cell lymphomas. Moreover, specific deubiquitinases (DUBs), such as A20 (TNFAIP3), OTULIN/ gumby, and CYLD, suppress NF-κB activation by a separate molecular basis, and genetic mutations of these DUBs cause disorders such as cancer. This review summarizes the various types of ubiquitination-mediated NF-κB regulation by E3s and DUBs. Moreover, the pathophysiological implications of these proteins, especially on inflammatory responses by cytokines and pathogens, are summarized.