Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation
Public Library of Science
MetadataShow full item record
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, ab and cd Tcell 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.
Fielding, C.A., Aicheler, R., Stanton, R.J., Wang, E.C., Han, S., Seirafian, S., Davies, J., McSharry, B.P., Weekes, M.P., Antrobus, P.R., Prod'homme, V., Blanchet, F.P., Sugrue, D., Cuff, S., Roberts, D., Davison, A.J., Lehner, P.J., Wilkinson, G.W. & Tomasec, P. (2014) 'Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation', PLoS Pathogens, 10(5), p.e1004058.
This article was published in PLOS Pathogens on 1 May 2014 (online), available open access at http://dx.doi.org/10.1371/journal.ppat.1004058
Showing items related by title, author, subject and abstract.
The maternal cardiovascular system at rest and in response to functional haemodynamic testing during healthy pregnancy Meah, Victoria L. (Cardiff Metropolitan University, 2017)Healthy pregnancy results in significant maternal cardiac adaptation to match the increased circulatory demands of the developing fetoplacental unit. Specifically, cardiac output, heart rate (HR), stroke volume (SV) and ...
Impaired myocardial function does not explain reduced left ventricular filling and stroke volume at rest or during exercise at high altitude Stembridge, Mike; Ainslie, Philip; Hughes, Michael G.; Stöhr, Eric J.; Cotter, James D.; Tymko, Michael M.; Day, Trevor A.; Bakker, Akke; Shave, Rob (American Physiological Society, 2015-11-15)Impaired myocardial systolic contraction and diastolic relaxation have been suggested as possible mechanisms contributing to the decreased stroke volume (SV) observed at high altitude (HA). To determine whether intrinsic ...
Dilatation and dysfunction of the right ventricle immediately after ultraendurance exercise: exploratory insights from conventional two-dimensional and speckle tracking echocardiography Oxborough, David; Shave, Rob; Warburton, Darren; Williams, Karen; Oxborough, Adele; Charlesworth, Sarah; Foulds, Heather; Hoffman, Martin D.; Birch, Karen; George, Keith (2011)Background—Running an ultramarathon has been shown to have a transient negative effect upon RV and LV function. Also, recent findings have suggested that ultra-endurance athletes may be more at risk of developing a "RV ...