Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance.
Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance.
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DOI：
10.1016/j.canlet.2020.12.002
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发表时间：
2021-04-01
期刊：
影响因子：
9.7
通讯作者：
Li, Shulin
中科院分区：
文献类型：
--
作者：
Hu, Jiemiao;Xia, Xueqing;Zhao, Qingnan;Li, Shulin
肿瘤细胞表面自然杀伤剂组 2 成员 D (NKG2D) 配体的脱落、表达缺失或内化会导致免疫逃避，这与癌症患者的不良预后相关。在许多癌症中，基质金属蛋白酶导致 NKG2D 配体蛋白水解脱落。然而，目前尚不清楚如何保护 NKG2D 配体不脱落。在这里，我们表明，两种关键的乙酰转移酶 GCN5 和 PCAF 可以阻止小鼠 NKG2D 配体 Rae-1 的脱落，它们乙酰化 Rae-1 的赖氨酸残基以避免体外和体内脱落。相反，Rae-1 赖氨酸 80 和 87 的突变消除了这种乙酰化，从而使肿瘤细胞对 NKG2D 依赖性免疫监视失去敏感性。值得注意的是，GCN5 的蛋白水平与人肿瘤组织微阵列中人 NKG2D 配体 ULPB1 的表达水平相关，更重要的是，与许多癌症的总体生存期延长相关。我们的结果表明，GCN5 和 PCAF 对 Rae-1 蛋白第 80 和 87 位赖氨酸进行乙酰化，可保护 Rae-1 免于脱落，从而激活 NKG2D 依赖性免疫监视。这一发现可能有助于揭示 NKG2D 免疫疗法在癌症治疗中的新靶点。
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.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1084/jem.20090225
发表时间：
2009-02-16
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Cerwenka A
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Cerwenka A
影响因子：
11.2
作者：
Ashiru O;Boutet P;Fernández-Messina L;Agüera-González S;Skepper JN;Valés-Gómez M;Reyburn HT
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Reyburn HT
影响因子：
4.4
作者：
Fionda, Cinzia;Soriani, Alessandra;Cippitelli, Marco
通讯作者：
Cippitelli, Marco
DOI：
10.1073/pnas.93.22.12445
发表时间：
1996-10-29
影响因子：
11.1
作者：
Groh, V;Bahram, S;Spies, T
通讯作者：
Spies, T