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) induce...
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2014
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oai:doaj.org-article:7136c5273c614b6592fe5fe8187ff4052021-11-18T06:06:37ZTwo novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation.1553-73661553-737410.1371/journal.ppat.1004058https://doaj.org/article/7136c5273c614b6592fe5fe8187ff4052014-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24787765/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374NKG2D 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.Ceri A FieldingRebecca AichelerRichard J StantonEddie C Y WangSong HanSepehr SeirafianJames DaviesBrian P McSharryMichael P WeekesP Robin AntrobusVirginie Prod'hommeFabien P BlanchetDaniel SugrueSimone CuffDawn RobertsAndrew J DavisonPaul J LehnerGavin W G WilkinsonPeter TomasecPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 5, p e1004058 (2014) |
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| collection |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Ceri A Fielding Rebecca Aicheler Richard J Stanton Eddie C Y Wang Song Han Sepehr Seirafian James Davies Brian P McSharry Michael P Weekes P Robin Antrobus Virginie Prod'homme Fabien P Blanchet Daniel Sugrue Simone Cuff Dawn Roberts Andrew J Davison Paul J Lehner Gavin W G Wilkinson Peter Tomasec Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| description |
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. |
| format |
article |
| author |
Ceri A Fielding Rebecca Aicheler Richard J Stanton Eddie C Y Wang Song Han Sepehr Seirafian James Davies Brian P McSharry Michael P Weekes P Robin Antrobus Virginie Prod'homme Fabien P Blanchet Daniel Sugrue Simone Cuff Dawn Roberts Andrew J Davison Paul J Lehner Gavin W G Wilkinson Peter Tomasec |
| author_facet |
Ceri A Fielding Rebecca Aicheler Richard J Stanton Eddie C Y Wang Song Han Sepehr Seirafian James Davies Brian P McSharry Michael P Weekes P Robin Antrobus Virginie Prod'homme Fabien P Blanchet Daniel Sugrue Simone Cuff Dawn Roberts Andrew J Davison Paul J Lehner Gavin W G Wilkinson Peter Tomasec |
| author_sort |
Ceri A Fielding |
| title |
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| title_short |
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| title_full |
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| title_fullStr |
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| title_full_unstemmed |
Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. |
| title_sort |
two novel human cytomegalovirus nk cell evasion functions target mica for lysosomal degradation. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/7136c5273c614b6592fe5fe8187ff405 |
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