TY - JOUR
T1 - Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance
AU - Hu, Jiemiao
AU - Xia, Xueqing
AU - Zhao, Qingnan
AU - Li, Shulin
N1 - Funding Information:
This study was supported by the National Institutes of Health through grant R01 CA200574 and Cancer Center Support Grant P30CA016672 . The following Cancer Center Support Grant core resources were used: Genetically Engineered Mouse Facility and Monoclonal Antibody Core Facility. The authors would like to thank Dr. Amy Ninetto from Scientific Publications, Research Medical Library, MD Anderson Cancer Center for editing the manuscript. The described research in this article is primarily supported by the research grants ( RO1CA120895 and R01CA200574 ) from National Cancer Institute of National Institutes of Health, United States .
Publisher Copyright:
© 2020 The Authors
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - Acetylation
KW - GCN5
KW - NKG2D ligand stabilization
KW - PCAF
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U2 - 10.1016/j.canlet.2020.12.002
DO - 10.1016/j.canlet.2020.12.002
M3 - Article
C2 - 33279621
AN - SCOPUS:85100046267
SN - 0304-3835
VL - 502
SP - 143
EP - 153
JO - Cancer Letters
JF - Cancer Letters
ER -