Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity

被引:51
作者
Tadagaki, Kenjiro [1 ,2 ,3 ]
Tudor, Daniela [1 ,2 ,3 ]
Gbahou, Florence [1 ,2 ,3 ]
Tschische, Pia [4 ]
Waldhoer, Maria [4 ]
Bomsel, Morgane [1 ,2 ,3 ]
Jockers, Ralf [1 ,2 ,3 ]
Kamal, Maud [1 ,2 ,3 ]
机构
[1] Inst Cochin, INSERM, U1016, F-75014 Paris, France
[2] CNRS, Unite Mixte Rech 8104, Paris, France
[3] Univ Paris 05, Paris, France
[4] Med Univ Graz, Inst Expt & Clin Pharmacol, Graz, Austria
基金
奥地利科学基金会;
关键词
PROTEIN-COUPLED RECEPTORS; US28; INFECTION; IDENTIFICATION; DIMERIZATION; PATHOGENESIS; INHIBITION; EXPRESSION; MOLECULE; CELLS;
D O I
10.1182/blood-2011-08-372516
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Human cytomegalovirus (HCMV) encodes four 7-transmembrane-spanning (7TM) proteins, US28, US27, UL33, and UL78, which present important sequence homology with human chemokine receptors. Whereas US28 binds a large range of chemokines and disturbs host cell signaling at different levels, the others are orphans with largely unknown functions. Assembly of 2 different 7TM proteins into hetero-oligomeric complexes may profoundly change their respective functional properties. We show that HCMV-encoded UL33 and UL78 form heteromers with CCR5 and CXCR4 chemokine receptors in transfected human embryonic kidney 293T cells and monocytic THP-1 cells. Expression of UL33 and UL78 had pleiotropic, predominantly negative, effects on CCR5 and CXCR4 cell surface expression, ligand-induced internalization, signal transduction, and migration without modifying the chemokine binding properties of CCR5 and CXCR4. Importantly, the coreceptor activity of CCR5 and CXCR4 for HIV was largely impaired in the presence of UL33 and UL78 without affecting expression of the primary HIV entry receptor CD4 and its interaction with CCR5 and CXCR4. Collectively, we identified the first molecular function for the HCMV-encoded orphan UL33 and UL78 7TM proteins, namely the regulation of cellular chemokine receptors through receptor heteromerization. (Blood. 2012; 119(21): 4908-4918)
引用
收藏
页码:4908 / 4918
页数:11
相关论文
共 48 条
[1]   An escort for GPCRs: implications for regulation of receptor density at the cell surface [J].
Achour, Lamia ;
Labbe-Jullie, Catherine ;
Scott, Mark G. H. ;
Marullo, Stefano .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2008, 29 (10) :528-535
[2]   CD4-CCR5 interaction in intracellular compartments contributes to receptor expression at the cell surface [J].
Achour, Lamia ;
Scott, Mark G. H. ;
Shirvani, Hamasseh ;
Thuret, Alain ;
Bismuth, Georges ;
Labbe-Jullie, Catherine ;
Marullo, Stefano .
BLOOD, 2009, 113 (09) :1938-1947
[3]   The R33 G protein-coupled receptor gene of rat cytomegalovirus plays an essential role in the pathogenesis of viral infection [J].
Beisser, PS ;
Vink, C ;
Van Dam, JG ;
Grauls, G ;
Vanherle, SJV ;
Bruggeman, CA .
JOURNAL OF VIROLOGY, 1998, 72 (03) :2352-2363
[4]   Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32 [J].
Benkirane, M ;
Jin, DY ;
Chun, RF ;
Koup, RA ;
Jeang, KT .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (49) :30603-30606
[5]  
Berger EA, 1997, AIDS, V11, pS3
[6]   The human cytomegalovirus-encoded receptor US28 increases the activity of the major immediate-early promoter/enhancer [J].
Boomker, Jasper M. ;
The, T. Hauw ;
de Leij, Lou F. M. H. ;
Harmsen, Martin C. .
VIRUS RESEARCH, 2006, 118 (1-2) :196-200
[7]   Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor [J].
Casarosa, P ;
Menge, WM ;
Minisini, R ;
Otto, C ;
van Heteren, J ;
Jongejan, A ;
Timmerman, H ;
Moepps, B ;
Kirchhoff, F ;
Mertens, T ;
Smit, MJ ;
Leurs, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (07) :5172-5178
[8]   Functional analysis of the murine cytomegalovirus chemokine receptor homologue M33: Ablation of constitutive signaling is associated with an attenuated phenotype in vivo [J].
Case, Ruth ;
Sharp, Emma ;
Benned-Jensen, Tau ;
Rosenkilde, Mette A. ;
Davis-Poynter, Nicholas ;
Farrell, Helen E. .
JOURNAL OF VIROLOGY, 2008, 82 (04) :1884-1898
[9]   HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV [J].
Cicala, Claudia ;
Arthos, James ;
Fauci, Anthony S. .
JOURNAL OF TRANSLATIONAL MEDICINE, 2011, 9
[10]   CXCR4-CCR5: A couple modulating T cell functions [J].
Contento, Rita Lucia ;
Molon, Barbara ;
Boularan, Cedric ;
Pozzan, Tullio ;
Manes, Santos ;
Marullo, Stefano ;
Viola, Antonella .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (29) :10101-10106