Linear ubiquitination: a novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex.
The NF-κB pathway is a central signaling pathway for inflammatory and immune responses, and aberrant NF-κB signaling is implicated multiple disorders, such as cancer and autoimmune, chronic inflammatory and metabolic diseases. NF-κB is regulated by various post-translational modifications, including phosphorylation and multiple ubiquitinations. We determined that LUBAC (linear ubiquitin chain assembly complex), composed of SHARPIN, HOIL-IL and HOIP, generates a novel type of Met1-linked linear polyubiquitin chain and specifically regulates the canonical NF-κB pathway via the linear ubiquitination of NEMO and RIP1. In the absence of LUBAC components, NF-κB signaling was attenuated and induced apoptosis and inflammation. Many studies on the pathophysiological functions of LUBAC, such as in B cell development, innate immune response, carcinogenesis, and osteogenesis, have been performed recently. This review summarizes these new findings on LUBAC- and linear ubiquitination-mediated NF-κB regulation and their implications in disorders.
Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan. ftokunaga@gunma-u.ac.jp
Fuminori
F
Tokunaga
Kazuhiro
K
Iwai
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007249:Inflammation / Q000209:etiology; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000209:etiology; D010012:Osteogenesis / Q000502:physiology; D025821:Polyubiquitin / Q000096:biosynthesis* / Q000378:metabolism; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
D019013:CD40 Antigens; D002352:Carrier Proteins; D016328:NF-kappa B; C575183:SHARPIN protein, human; D014157:Transcription Factors; D025801:Ubiquitin; D014452:Ubiquitins; D025821:Polyubiquitin; C504507:RBCK1 protein, human; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases