直鎖状ポリユビキチン化：NF-κB活性化に必須な新たなユビキチン修飾系

抄録

The ubiquitin system plays crucial roles in a wide variety of biological phenomena by regulating the function of proteins via conjugation of polyubiquitin chains. Types of polyubiquitin chains have been reported to determine the mode of regulation of proteins. Ubiquitin contains seven lysine (Lys) residues and ubiquitin molecules can form different types of chains via isopeptide bonds between an internal Lys and the C-terminal glycine. We have reported that a protein complex composed of two RING finger proteins, HOIL-1L and HOIP, specifically conjugates a novel type of polyubiquitin chain in which the ubiquitin moieties are linked via a head-to-tail linear linkage. We then designated the complex composed of HOIL-1L and HOIP as LUBAC (linear ubiquitin chain assembly complex). Through the analyses to elucidate physiological roles of the linear polyubiquitin chain, we have found that LUBAC specifically activates the NF-κB pathway. LUBAC binds to NF-kappaB essential modulator (NEMO) and conjugates linear polyubiquitin chains onto NEMO following stimulation with inflammatory cytokines. Moreover, deletion of HOIL-1L suppresses TNF-alpha-induced NF-kappaB activation and enhances Jun N-terminal kinase (JNK)-mediated apoptosis in mouse hepatocytes and embryonic fibroblasts. These results clearly indicate that LUBAC regulates TNF-alpha-mediated NF-kappaB activation via signal-dependent association and linear polyubiquitination of NEMO.