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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-07-2158.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2858-2864
RED CELLS
A single viral protein HCMV US2 affects antigen presentation and
intracellular iron homeostasis by degradation of classical HLA class I
and HFE molecules
Sayeh Vahdati-Ben Arieh,
Nihay Laham,
Chana Schechter,
Jon W. Yewdell,
John E. Coligan, and
Rachel Ehrlich
From the Department of Cell Research and Immunology,
The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel
Aviv, Israel; Laboratory of Viral Diseases, National Institute of
Allergy and Infectious Diseases (NIAID), National Institutes of Health
(NIH), Bethesda, MD; and Laboratory of Allergic Diseases, NIAID, NIH,
Bethesda, MD.
HFE is a nonclassical class I molecule that associates with
 2-microglobulin (2m) and with the transferrin receptor.
HFE accumulates in transferrin-containing endosomes, and its
overexpression in human cell lines correlates with decreased
transferrin receptor (TFR)-mediated iron uptake and decreased
intracellular iron pools. A mutation that interferes with proper
folding and assembly of HFE complexes results in a severe iron-overload
disease hereditary hemochromatosis. We previously suggested that
viruses could also interfere with iron metabolism through the
production of proteins that inactivate HFE, similarly to classical
class I proteins. In particular, we demonstrated in a transient
expression system that human cytomegalovirus (HCMV) US2 targeted HFE
for proteasomal degradation. Here we demonstrate that the
stable expression of HCMV US2 in HEK 293 cells constitutively
expressing HFE leads to loss of HFE expression both intracellularly and
on the cell surface, and the significant reduction of classical class I
expression. Both HFE and classical class I molecules are
targeted to degradation via a similar pathway. This HCMV US2-mediated
degradation of HFE leads to increased intracellular iron pools as
indicated by reduced synthesis of TfR and increased ferritin synthesis.
Whether this interference with regulation of iron metabolism
potentiates viral replication and/or promotes damage of HCMV-infected
tissues remains to be determined. Nevertheless, the deleterious effect
of US2 on the expression of HFE and classical class I major
histo-compatibility complexes (MHC) provides HCMV with an efficient
tool for altering cellular metabolic functions, as well as supporting
the escape of virus-infected cells from cytotoxic T lymphocyte
(CTL)-mediated immune responses.
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