title: Generation of free ubiquitin chains is up-regulated in stress and facilitated by the HECT domain ubiquitin ligases UFD4 and HUL5.
abstract: Polyubiquitin chains serve a variety of physiological roles. Typically the chains are bound covalently to a protein substrate and in many cases target it for degradation by the 26S proteasome. However, several studies have demonstrated the existence of free polyubiquitin chains which are not linked to a specific substrate. Several physiological functions have been attributed to these chains, among them playing a role in signal transduction and serving as storage of ubiquitin for utilization under stress. In the present study, we have established a system for the detection of free ubiquitin chains and monitoring their level under changing conditions. Using this system, we show that UFD4 (ubiquitin fusion degradation 4), a HECT (homologous with E6-AP C-terminus) domain ubiquitin ligase, is involved in free chain generation. We also show that generation of these chains is stimulated in response to a variety of stresses, particularly those caused by DNA damage. However, it appears that the stress-induced synthesis of free chains is catalyzed by a different ligase, HUL5 (HECT ubiquitin ligase 5), which is also a HECT domain E3.
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Efron Street, P.O. Box 9649, Haifa 31096, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Braten
authors.forename: Nitzan
authors.initials: N
authors.lastname: Shabek
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kravtsova-Ivantsiv
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
mesh_terms: D002384:Catalysis; D057809:HEK293 Cells; D006801:Humans; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis*; D013312:Stress, Physiological / Q000502:physiology*; D025801:Ubiquitin / Q000096:biosynthesis*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C468547:HUL5 protein, S cerevisiae; C509339:Ufd4 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases