title: Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.
abstract: ISG15 conjugation (ISGylation) to proteins is a multistep process involving interferon (IFN)-inducible UBE1L (E1), UbcH8 (E2), and ISG15 E3 ligases (E3s). Studies performed over the past several years have shown that ISGylation plays a pivotal role in the host antiviral response against certain viruses. Recent in vitro studies revealed that human Herc5 and mouse Herc6 are major ISG15 E3 ligases, respectively. However, the global function of Herc5/6 proteins in vivo still remains unclear. Here, we report generation and initial characterization of Herc6 knockout mice. Substantial reductions of ISGylation were observed in Herc6-deficient cells after polyinosinic-polycytidylic acid double-stranded RNA injection of mice or IFN treatment of cells. On the other hand, Herc6-deficient cells and wild-type (WT) cells had similar responses to IFN stimulation, Sendai virus (Z strain) infection, and vesicular stomatitis virus infection. These results indicate that Herc6 does not play a critical role in antiviral defense of these viral infections in mice. Interestingly, male Herc6-deficient mice showed seminal vesicle hypertrophy. No such problem was detected in WT and ISG15 activating enzyme Ube1L-deficient mice. These results suggest that in addition to promoting protein ISGylation, Herc6 has a novel and protein ISGylation-independent function in the male reproductive system.
authors.affiliation: 1 Moores UCSD Cancer Center, University of California , San Diego, La Jolla, California.
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Arimoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Chuyi
authors.initials: C
authors.lastname: Cheng
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Fan
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
mesh_terms: D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D005822:Genetic Vectors / Q000235:genetics; D006984:Hypertrophy; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012669:Seminal Vesicles / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D054243:Vesicular Stomatitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D014452:Ubiquitins; D007372:Interferons; C570816:HERC6 protein, mouse; D044767:Ubiquitin-Protein Ligases; D044764:Ubiquitin-Activating Enzymes