Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis.
HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/beta2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.
Ben-Arieh
S V
SV
Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Zimerman
B
B
Smorodinsky
N I
NI
Yaacubovicz
M
M
Schechter
C
C
Bacik
I
I
Gibbs
J
J
Bennink
J R
JR
Yewdell
J W
JW
Coligan
J E
JE
Firat
H
H
Lemonnier
F
F
Ehrlich
R
R
D000595:Amino Acid Sequence; D003587:Cytomegalovirus / Q000502:physiology*; D006680:HLA Antigens / Q000378:metabolism*; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016601:RNA-Binding Proteins / Q000502:physiology; D011990:Receptors, Transferrin / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology
C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D007501:Iron