Related Human Cytomegalovirus Genes US18 and US20 Target MICA for Lysosomal Degradation
Ceri
A.
Fielding1*,
Rebecca
Aicheler1,
Richard
Stanton1,
Edward
Wang1,
Sepehr
Seirafian1,
James
Davies1,
Brian
McSharry1,
Robin
Antrobus2,
Michael
Weekes2,
Virginie
Prod'Homme1,
Fabian
Blanchet3,
Daniel
Sugrue1,
Simone
Cuff1,
Dawn
Roberts1,
Andrew
Davison4,
Paul
Lehner2,
Gavin
Wilkinson1 and
Peter
Tomasec1
-
1
Cardiff University, Cardiff Institute of Infection and Immunity, United Kingdom
-
2
University of Cambridge, Cambridge Institute for Medical Research, United Kingdom
-
3
Cardiff University, Cardiff Institute of Infection and Immunity, United Kingdom
-
4
University of Glasgow, MRC Centre for Virus Research, United Kingdom
NK cells play a crucial role in controlling human cytomegalovirus (HCMV) infection. The activating receptor NKG2D is expressed by all NK cells and binds 8 different ligands: MICA and MICB, and ULBP 1-6. In its turn, HCMV is known to encode at least 3 genes that target NKG2D ligands (i) UL16 sequesters MICB, ULBP1, 2, 4 and 6 in the ER (ii) UL142 retains MICA in the Golgi and (iii) the microRNA miR-UL112 suppresses MICB expression . Our studies using viral deletion mutants revealed that HCMV encoded functions, in addition to UL142, that targeted MICA. MICA expression during virus infection could be rescued by by lysosomal inhibitors. The function was first mapped to the US18-22 gene region by screening HCMV mutants with deletions in genomic ‘blocks’, and then to both US18 and US20 using a panel of Ad recombinants. The two genes were capable of acting independently, yet in combination clearly co-operated in both the suppression of MICA expression and NK cell activation. US18 and US20 are both members of the US12 gene family. All 12 members of the US12 family are arranged consecutively on the genome and constitute an ancient viral genomic expansion or ‘accordion’ potentially selected to enhance HCMV immune evasion. This gene family is defined by 7 transmembrane-spanning domains and have homology with the cellular TMBIMs (transmembrane bax-inhibitor 1 motif-containing proteins), excepting US19. This study provides the first insight into the function of the US12 gene family and potentially for its expansion in primate cytomegaloviruses.
Acknowledgements
I would like to acknowledge funding from the Medical Research Council (MRC) UK and the support of a British Society of Immunology (BSI) ICI 2013 Travel Award.
Keywords:
NK cells,
NKG2D receptor,
Cytomegalovirus Infections,
hcmv,
MICA
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Fielding
CA,
Aicheler
R,
Stanton
R,
Wang
E,
Seirafian
S,
Davies
J,
McSharry
B,
Antrobus
R,
Weekes
M,
Prod'Homme
V,
Blanchet
F,
Sugrue
D,
Cuff
S,
Roberts
D,
Davison
A,
Lehner
P,
Wilkinson
G and
Tomasec
P
(2013). Related Human Cytomegalovirus Genes US18 and US20 Target MICA for Lysosomal Degradation.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00493
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Received:
10 Apr 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Ceri A Fielding, Cardiff University, Cardiff Institute of Infection and Immunity, Cardifff, Wales, CF14 4XN, United Kingdom, fieldingca@cf.ac.uk