Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
EMBO Rep. 2019 Jul;20(7):e47352. doi: 10.15252/embr.201847352. Epub 2019 May 24.
Melanoma antigen genes (MAGEs) are emerging as important oncogenic drivers that are normally restricted to expression in male germ cells but are aberrantly expressed in cancers and promote tumorigenesis. Mechanistically, MAGEs function as substrate specifying subunits of E3 ubiquitin ligases. Thus, the activation of germline-specific genes in cancer can drive metabolic and signaling pathways through altered ubiquitination to promote tumorigenesis. However, the mechanisms regulating MAGE expression and activity are unclear. Here, we describe how the MAGE-A3/6 proteins that function as repressors of autophagy are downregulated in response to nutrient deprivation. Short-term cellular starvation promotes rapid MAGE-A3/6 degradation in a proteasome-dependent manner. Proteomic analysis reveals that degradation of MAGE-A3/6 is controlled by the CRL4-DCAF12 E3 ubiquitin ligase. Importantly, the degradation of MAGE-A3/6 by CRL4-DCAF12 is required for starvation-induced autophagy. These findings suggest that oncogenic MAGEs can be dynamically controlled in response to stress to allow cellular adaptation, autophagy regulation, and tumor growth and that CRL4-DCAF12 activity is responsive to nutrient status.
黑色素瘤相关抗原基因（MAGEs）作为重要的致癌驱动基因正在被逐渐认识，这些基因通常局限于雄性生殖细胞中的表达，但在癌症中异常表达并促进肿瘤发生。从机制上讲，MAGEs 作为 E3 泛素连接酶的底物特异性亚基发挥作用。因此，癌症中生殖系特异性基因的激活可以通过改变泛素化来驱动代谢和信号通路，从而促进肿瘤发生。然而，调节 MAGE 表达和活性的机制尚不清楚。在这里，我们描述了在营养物质缺乏的情况下，作为自噬抑制剂的 MAGE-A3/6 蛋白如何下调。短期细胞饥饿以依赖蛋白酶体的方式促进 MAGE-A3/6 的快速降解。蛋白质组学分析表明，MAGE-A3/6 的降解受 CRL4-DCAF12 E3 泛素连接酶的控制。重要的是，CRL4-DCAF12 介导的 MAGE-A3/6 降解是饥饿诱导自噬所必需的。这些发现表明，致癌性 MAGEs 可以根据应激条件进行动态调控，以允许细胞适应、自噬调控以及肿瘤生长，并且 CRL4-DCAF12 的活性对营养状态有响应。
