The human cytomegalovirus protein UL148A downregulates the NK cell-activating ligand MICA to avoid NK cell attack

Liat Dassa, Einat Seidel, Esther Oiknine-Djian, Rachel Yamin, Dana G. Wolf, Vu Thuy Khanh Le-Trilling*, Ofer Mandelboim

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune system capable of killing hazardous cells, including virally infected cells. NK cell-mediated killing is triggered by activating receptors. Prominent among these is the activating receptor NKG2D, which binds several stress-induced ligands, among them major histocompatibility complex (MHC) class I-related chain A (MICA). Most of the human population is persistently infected with human cytomegalovirus (HCMV), a virus which employs multiple immune evasion mechanisms, many of which target NK cell responses. HCMV infection is mostly asymptomatic, but in congenitally infected neonates and in immunosuppressed patients it can lead to serious complications and mortality. Here we discovered that an HCMV protein named UL148A whose role was hitherto unknown is required for evasion of NK cells. We demonstrate that UL148A-deficient HCMV strains are impaired in their ability to downregulate MICA expression. We further show that when expressed by itself, UL148A is not sufficient for MICA targeting, but rather acts in concert with an unknown viral factor. Using inhibitors of different cellular degradation pathways, we show that UL148A targets MICA for lysosomal degradation. Finally, we show that UL148Amediated MICA downregulation hampers NK cell-mediated killing of HCMV-infected cells. Discovering the full repertoire of HCMV immune evasion mechanisms will lead to a better understanding of the ability of HCMV to persist in the host and may also promote the development of new vaccines and drugs against HCMV.

Original languageAmerican English
Article numbere00162-18
JournalJournal of Virology
Volume92
Issue number17
DOIs
StatePublished - 1 Sep 2018

Bibliographical note

Publisher Copyright:
© 2018 American Society for Microbiology.

Keywords

  • HCMV
  • Immune evasion
  • NK cells

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