A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules.
HFE is a nonclassical class I molecule that associates with beta 2-microglobulin (beta 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.
Vahdati-Ben Arieh
Sayeh
S
Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Laham
Nihay
N
Schechter
Chana
C
Yewdell
Jon W
JW
Coligan
John E
JE
Ehrlich
Rachel
R
D017951:Antigen Presentation / Q000187:drug effects*; D002460:Cell Line; D003587:Cytomegalovirus / Q000737:chemistry / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006680:HLA Antigens / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D014162:Transfection; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology*
C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D005293:Ferritins; D007501:Iron