title: The stability of herpes simplex virus 1 ICP0 early after infection is defined by the RING finger and the UL13 protein kinase.
abstract: Herpes simplex virus 1 (HSV-1)-infected cell protein 0 (ICP0) is a multifunctional protein that plays a key role in overcoming numerous facets of host innate immunity. A key function of ICP0 that requires an intact RING finger domain is that of an ubiquitin E3 ligase: ICP0 interacts with at least three ubiquitin-conjugating enzymes of which one, UbcH5a, is required for degradation of PML and SP100. A preceding report showed that ICP0 is highly unstable at very early times after infection but becomes stable at later times. We report here that (i) the degradation of ICP0 is not infected cell specific, (ii) the degradation does not require the interaction of ICP0 with either UbcH5a, UbcH6, or UbcH9, (iii) ICP0 is degraded both early and late in cells infected with a mutant lacking the UL13 protein kinase, (iv) ICP0 encoded by wild-type virus or the ΔUL13 mutant is stable in cells transfected with a plasmid encoding UL13 before infection, (v) ICP0 carrying mutations in the RING finger domain is stable both early and late in infection, and, finally, (vi) in cells infected with both wild type and RING finger mutant only the wild-type ICP0 is rapidly degraded at early times. The results suggest that the stability of ICP0 is mediated by the UL13 protein kinase and that the target of proteolysis is a site at or near the RING domain of ICP0.
  
  
  OBJECTIVE
  ICP0, a major regulatory protein of HSV-1, turns over rapidly early in infection but becomes stable at late times. We report that stabilization requires the presence of UL13 protein kinase and that an ICP0 with mutations in RING finger is stable. In mixed infections mutant ICP0 is stable, whereas the wild-type ICP0 is degraded. Our findings suggest that the lifestyle of HSV-1 requires an ICP0 that turns over rapidly if late proteins are absent.
authors.affiliation: The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhu
authors.forename: Te
authors.initials: T
authors.lastname: Du
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhou
authors.forename: Bernard
authors.initials: B
authors.lastname: Roizman
mesh_terms: D000818:Animals; D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D059748:Proteolysis; D054829:RING Finger Domains; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D017874:Immediate-Early Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D011494:Protein Kinases; C082380:UL13 protein, Simplexvirus