Immunology Programme, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.
J Immunol. 2012 Aug 15;189(4):1826-34. doi: 10.4049/jimmunol.1200965. Epub 2012 Jul 13.
NK cells play a crucial role in innate immunity against tumors. In many human tumors, Ras is chronically active, and tumor cells frequently express ligands for the activating NK cell receptor NKG2D. In this study, we report that Ras activation upregulates the expression of Raet1 protein family members Rae1α and Rae1β in mouse and ULBP1-3 in human cells. In addition, Ras also induced MHC class I chain-related protein expression in some human cell lines. Overexpression of the constitutively active H-RasV12 mutant was sufficient to induce NKG2D ligand expression. H-RasV12-induced NKG2D ligand upregulation depended on Raf, MAPK/MEK, and PI3K, but not ATM or ATR, two PI3K-like kinases previously shown to induce NKG2D ligand expression. Analysis of the 5' untranslated regions of Raet1 family members suggested the presence of features known to impair translation initiation. Overexpression of the rate-limiting translation initiation factor eIF4E induced Rae1 and ULBP1 expression in a Ras- and PI3K-dependent manner. Upregulation of NKG2D ligands by H-RasV12 increased sensitivity of cells to NK cell-mediated cytotoxicity. In summary, our data suggest that chronic Ras activation is linked to innate immune responses, which may contribute to immune surveillance of H-Ras transformed cells.
自然杀伤（NK）细胞在抗肿瘤固有免疫中发挥着关键作用。在许多人类肿瘤中，Ras 持续激活，肿瘤细胞经常表达激活 NK 细胞受体 NKG2D 的配体。在这项研究中，我们报告 Ras 激活可上调小鼠的 Raet1 蛋白家族成员 Rae1α 和 Rae1β 以及人细胞中的 ULBP1-3 的表达。此外，Ras 还可诱导一些人细胞系中 MHC Ⅰ类链相关蛋白的表达。组成型激活的 H-RasV12 突变体的过表达足以诱导 NKG2D 配体的表达。H-RasV12 诱导的 NKG2D 配体上调依赖于 Raf、MAPK/MEK 和 PI3K，但不依赖于 ATM 或 ATR，这两种 PI3K 样激酶先前已被证明可诱导 NKG2D 配体的表达。Raet1 家族成员 5'非翻译区的分析表明存在已知会损害翻译起始的特征。限速翻译起始因子 eIF4E 的过表达以 Ras 和 PI3K 依赖的方式诱导 Rae1 和 ULBP1 的表达。H-RasV12 上调 NKG2D 配体增加了细胞对 NK 细胞介导的细胞毒性的敏感性。总之，我们的数据表明慢性 Ras 激活与先天免疫反应有关，这可能有助于对 H-Ras 转化细胞的免疫监视。
