Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance

Jiemiao Hu, Xueqing Xia, Qingnan Zhao, Shulin Li

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Shedding, loss of expression, or internalization of natural killer group 2, member D (NKG2D) ligands from the tumor cell surface leads to immune evasion, which is associated with poor prognosis in patients with cancer. In many cancers, matrix metalloproteinases cause the proteolytic shedding of NKG2D ligands. However, it remained unclear how to protect NKG2D ligands from shedding. Here, we showed that the shedding of the mouse NKG2D ligand Rae-1 can be prevented by two critical acetyltransferases, GCN5 and PCAF, which acetylate the lysine residues of Rae-1 to avoid shedding both in vitro and in vivo. In contrast, mutations at lysines 80 and 87 of Rae-1 abrogated this acetylation and thereby desensitized tumor cells to NKG2D-dependent immune surveillance. Notably, the protein levels of GCN5 correlated with the expression levels of the human NKG2D ligand ULPB1 in a human tumor tissue microarray and, more importantly, with prolonged overall survival in many cancers. Our results suggest that the acetylation of Rae-1 protein at lysines 80 and 87 by GCN5 and PCAF protects Rae-1 from shedding so as to activate NKG2D-dependent immune surveillance. This discovery may shed light on new targets for NKG2D immunotherapy in cancer treatment.

Original languageEnglish (US)
Pages (from-to)143-153
Number of pages11
JournalCancer Letters
Volume502
DOIs
StatePublished - Apr 1 2021

Keywords

  • Acetylation
  • GCN5
  • NKG2D ligand stabilization
  • PCAF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Monoclonal Antibody Facility
  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core
  • Genetically Engineered Mouse Facility
  • Research Animal Support Facility

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