Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation.
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Ceri A
CA
Fielding
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Rebecca
R
Aicheler
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Richard J
RJ
Stanton
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Eddie C Y
EC
Wang
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Song
S
Han
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Sepehr
S
Seirafian
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
James
J
Davies
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Brian P
BP
McSharry
Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, United Kingdom.
Michael P
MP
Weekes
Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, United Kingdom.
P Robin
PR
Antrobus
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Virginie
V
Prod'homme
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Fabien P
FP
Blanchet
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Daniel
D
Sugrue
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Simone
S
Cuff
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Dawn
D
Roberts
MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
Andrew J
AJ
Davison
Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, United Kingdom.
Paul J
PJ
Lehner
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Gavin W G
GW
Wilkinson
Section of Medical Microbiology, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Peter
P
Tomasec
D000328:Adult; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology / Q000472:pathogenicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007976:Leupeptins / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000502:physiology; D059748:Proteolysis / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000502:physiology*
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D007976:Leupeptins; D008164:Luminescent Proteins; C099187:MHC class I-related chain A; D018942:Macrolides; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins; C000598515:US18 protein, human cytomegalovirus; C000598516:US20 protein, human cytomegalovirus; D014764:Viral Proteins; C054562:yellow fluorescent protein, Bacteria; C036978:concanamycin A; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde