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The HHV-6B U20 glycoprotein binds ULBP1, masking it from recognition by NKG2D and interfering with natural killer cell activation

Journal Article · · Frontiers in Immunology
 [1];  [2];  [1];  [1];  [3];  [1]
  1. University of Massachusetts Chan Medical School, Worcester, MA (United States)
  2. Medical College of Wisconsin, Milwaukee, WI (United States); Carroll University, Waukesha, WI (United States)
  3. Medical College of Wisconsin, Milwaukee, WI (United States)
+ Show Author Affiliations
Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined. We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches. We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 – ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States). Center for BioMolecular Structure (CBMS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
SC0012704
OSTI ID:
2470306
Journal Information:
Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 15; ISSN 1664-3224
Publisher:
Frontiers Research FoundationCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
Immunology
human herpesvirus
immune evasion
major histocompatibility complex
natural killer cell ligand
small-angle X-ray scattering
stress receptor
surface masking