title: The Major Immediate-Early Protein IE2 of HumanCytomegalovirusIs Sufficient to Induce Proteasomal Degradation of CD83 on Mature Dendritic Cells.
abstract: Human cytomegalovirus (HCMV) is the prototypic beta-herpesvirus and widespread throughout the human population. While infection is asymptomatic in healthy individuals, it can lead to high morbidity and mortality in immunocompromised persons. Importantly, HCMV evolved multiple strategies to interfere with immune cell function in order to establish latency in infected individuals. As mature DCs (mDCs) are antigen-presenting cells able to activate naïve T cells they play a crucial role during induction of effective antiviral immune responses. Interestingly, earlier studies demonstrated that the functionally important mDC surface molecule CD83 is down-regulated upon HCMV infection resulting in a reduced T cell stimulatory capacity of the infected cells. However, the viral effector protein and the precise mechanism of HCMV-mediated CD83 reduction remain to be discovered. Using flow cytometric analyses, we observed significant down-modulation of CD83 surface expression becoming significant already 12 h after HCMV infection. Moreover, Western bot analyses revealed that, in sharp contrast to previous studies, loss of CD83 is not restricted to the membrane-bound molecule, but also occurs intracellularly. Furthermore, inhibition of the proteasome almost completely restored CD83 surface expression during HCMV infection. Results of infection kinetics and cycloheximide-actinomycin D-chase experiments, strongly suggested that an HCMV immediate early gene product is responsible for the induction of CD83 down-modulation. Consequently, we were able to identify the major immediate early protein IE2 as the viral effector protein that induces proteasomal CD83 degradation.
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Heilingloh
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Grosche
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Kummer
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Mühl-Zürbes
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kamm
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg Erlangen, Germany.
authors.forename: Myriam
authors.initials: M
authors.lastname: Scherer
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Latzko
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.affiliation: Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
keywords: CD83; HCMV; IE2; dendritic cells; proteasomal degradation