A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions.
The E3 transcription unit of human adenoviruses (Ads) encodes immunomodulatory proteins. Interestingly, the size and composition of the E3 region differs considerably among Ad species, suggesting that distinct sets of immunomodulatory E3 proteins may influence their interaction with the human host and the disease pattern. However, to date, only common immune evasion functions of species C E3 proteins have been described. Here we report on the immunomodulatory activity of a species D-specific E3 protein, E3/49K. Unlike all other E3 proteins that act on infected cells, E3/49K seems to target uninfected cells. Initially synthesized as an 80- to 100-kDa type I transmembrane protein, E3/49K is subsequently cleaved, with the large ectodomain (sec49K) secreted. We found that purified sec49K exhibits specific binding to lymphoid cell lines and all primary leukocytes, but not to fibroblasts or epithelial cells. Consistent with this binding profile and the molecular mass, the sec49K receptor was identified as the cell surface protein tyrosine phosphatase CD45. Antibody-blocking studies suggested that sec49K binds to the membrane proximal domains present in all CD45 isoforms. Functional studies showed that sec49K can suppress the activation and cytotoxicity of natural killer cells as well as the activation, signaling, and cytokine production of T cells. Thus, we have discovered an adenovirus protein that is actively secreted and describe immunomodulatory activities of an E3 protein uniquely expressed by a single Ad species.
School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom.
Mark
M
Windheim
Jennifer H
JH
Southcombe
Elisabeth
E
Kremmer
Lucy
L
Chaplin
Doris
D
Urlaub
Christine S
CS
Falk
Maren
M
Claus
Janine
J
Mihm
Myles
M
Braithwaite
Kevin
K
Dennehy
Harald
H
Renz
Martina
M
Sester
Carsten
C
Watzl
Hans-Gerhard
HG
Burgert
D017503:Adenovirus E3 Proteins / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D057809:HEK293 Cells; D006801:Humans; D056747:Immunomodulation / Q000276:immunology*; D047468:Immunoprecipitation; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism
D017503:Adenovirus E3 Proteins; D017493:Leukocyte Common Antigens
Ad19a/Ad64; E3 protein shedding; epidemic keratoconjunctivitis; subversion of leukocytes