title: Herpes simplex virus type 1 ICP0 induces CD83 degradation in mature dendritic cells independent of its E3 ubiquitin ligase function.
abstract: Mature dendritic cells (mDCs) are the most potent antigen-presenting cells known today, as they are the only antigen-presenting cells able to induce naïve T-cells. Therefore, they play a crucial role during the induction of effective antiviral immune responses. Interestingly, the surface molecule CD83 expressed on mDCs is targeted by several viruses. As CD83 has been shown to exert co-stimulatory functions on mDCs, its downmodulation represents a viral immune escape mechanism. Mechanistically, it has been shown that herpes simplex virus type 1 infection leads to proteasomal degradation of CD83, resulting in a strongly diminished T-cell stimulatory capacity of the infected mDC. Previous data suggest that the viral immediate-early protein ICP0 (infected-cell protein 0) plays an important role in this process. In the present study, we showed that ICP0 is sufficient to induce CD83 degradation in the absence of any other viral factor. However, the mechanism of ICP0-mediated CD83 degradation is not yet understood. Here, we provide evidence that ubiquitination of lysine residues is, despite the published E3 ubiquitin ligase activity of ICP0, not necessary for CD83 degradation. This finding was underlined by the observation that expression of an ICP0 mutant lacking the E3 ubiquitin ligase domain in mDCs still induced CD83 degradation. Finally, inhibition of E1 activating enzyme using the specific inhibitor 4[4-(5-nitro-furan-2-ylmethylene)-3.5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester did not prevent CD83 degradation. Taken together, our data provide strong evidence that ICP0 alone induces CD83 degradation independent of its E3 ubiquitin ligase function and of the ubiquitin machinery.
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Heilingloh
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Mühl-Zürbes
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Kummer
mesh_terms: D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005814:Genes, Viral; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology*; D057131:Immune Evasion / Q000235:genetics; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D017874:Immediate-Early Proteins; D007136:Immunoglobulins; D008239:Lysine; D008562:Membrane Glycoproteins; D046988:Proteasome Endopeptidase Complex; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C051804:Vmw110 protein, Human herpesvirus 1