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) molecu le that is mutated in the autosomal recessive iron overload disease heredit ary 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 demonstr ate the expression of stable and fully glycosylated TfR-free and TfR-associ ated hHFE/beta 2m complexes. We show that both the stability and assembly o f hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MH C molecules. HCMV US2, but not US11, targets FIFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron m etabolism by a viral protein is a means of potentiating viral replication r emains to be determined. The reduced expression of classical class I MHC an d FIFE complexes provides the virus with an efficient tool for altering cel lular metabolism and escaping certain immune responses.