title: Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain.
abstract: Viral hijacking of cellular processes relies on the ability to mimic the structure or function of cellular proteins. Many viruses encode ubiquitin ligases to facilitate infection, although the mechanisms by which they select their substrates are often unknown. The Herpes Simplex Virus type-1-encoded E3 ubiquitin ligase, ICP0, promotes infection through degradation of cellular proteins, including the DNA damage response E3 ligases RNF8 and RNF168. Here we describe a mechanism by which this viral E3 hijacks a cellular phosphorylation-based targeting strategy to degrade RNF8. By mimicking a cellular phosphosite, ICP0 binds RNF8 via the RNF8 forkhead associated (FHA) domain. Phosphorylation of ICP0 T67 by CK1 recruits RNF8 for degradation and thereby promotes viral transcription, replication, and progeny production. We demonstrate that this mechanism may constitute a broader viral strategy to target other cellular factors, highlighting the importance of this region of the ICP0 protein in countering intrinsic antiviral defenses.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Mira S
authors.initials: MS
authors.lastname: Chaurushiya
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Lilley
authors.forename: Aaron
authors.initials: A
authors.lastname: Aslanian
authors.forename: Jill
authors.initials: J
authors.lastname: Meisenhelder
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Scott
authors.forename: Sébastien
authors.initials: S
authors.lastname: Landry
authors.forename: Simina
authors.initials: S
authors.lastname: Ticau
authors.forename: Chris
authors.initials: C
authors.lastname: Boutell
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Weitzman
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D018716:Molecular Mimicry / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D014158:Transcription, Genetic / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C486521:RNF8 protein, human; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1