|
|
Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-07-2158.
Submitted July 18, 2002
Accepted November 13, 2002
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*
Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
Laboratory of Viral Diseases, NIAID, Bethesda, MD, USA
Laboratory of Allergic Diseases, NIAID, Rockville, MD, USA
* Corresponding author; email: rachele{at}post.tau.ac.il.
HFE is a non-classical class I molecule that associates with  2m and with the transferrin receptor. HFE accumulates in transferrin-containing endosomes and its over-expression in human cell lines correlates with decreased transferrin receptor-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 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 MHC complexes provides HCMV with an efficient tool for altering cellular metabolic functions, as well as supporting the escape of virus-infected cells from CTL-mediated immune responses.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. N. Hebert and M. Molinari
In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases
Physiol Rev,
October 1, 2007;
87(4):
1377 - 1408.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. F. de Almeida, J. V. Fleming, J. E. Azevedo, M. Carmo-Fonseca, and M. de Sousa
Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression
J. Immunol.,
March 15, 2007;
178(6):
3612 - 3619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Thilo, P. Berglund, S. E. Applequist, J. W. Yewdell, H.-G. Ljunggren, and A. Achour
Dissection of the Interaction of the Human Cytomegalovirus-derived US2 Protein with Major Histocompatibility Complex Class I Molecules: PROMINENT ROLE OF A SINGLE ARGININE RESIDUE IN HUMAN LEUKOCYTE ANTIGEN-A2
J. Biol. Chem.,
March 31, 2006;
281(13):
8950 - 8957.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. F. de Almeida, I. F. Carvalho, C. S. Cardoso, J. V. Cordeiro, J. E. Azevedo, J. Neefjes, and M. de Sousa
HFE cross-talks with the MHC class I antigen presentation pathway
Blood,
August 1, 2005;
106(3):
971 - 977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Pascolo, F. Ginhoux, N. Laham, S. Walter, O. Schoor, J. Probst, P. Rohrlich, F. Obermayr, P. Fisch, O. Danos, et al.
The non-classical HLA class I molecule HFE does not influence the NK-like activity contained in fresh human PBMCs and does not interact with NK cells
Int. Immunol.,
February 1, 2005;
17(2):
117 - 122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Salerno-Goncalves, M. Fernandez-Vina, D. M. Lewinsohn, and M. B. Sztein
Identification of a Human HLA-E-Restricted CD8+ T Cell Subset in Volunteers Immunized with Salmonella enterica Serovar Typhi Strain Ty21a Typhoid Vaccine
J. Immunol.,
November 1, 2004;
173(9):
5852 - 5862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. E. Crowe, L. M. Maglova, P. Ponka, and J. M. Russell
Human cytomegalovirus-induced host cell enlargement is iron dependent
Am J Physiol Cell Physiol,
October 1, 2004;
287(4):
C1023 - C1030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
