丙肝病毒调节葡萄糖转运蛋白1运输的研究

Hepatitis C virus (HCV) induces the defect of glucose uptake in host cells. Glucose transporter 1 (GLUT1) is an important transporter protein for glucose, however, little is known about whether the cell surface level of GLUT1 is regulated by HCV. Based on our preliminary results, we propose the following hypothesis. By association with SNX27, HCV proteins reduce the interaction between SNX27 and VPS26. Thus, the transport of GLUT1 from endosome to cell surface is inhibited by HCV. As a result, HCV could reduce glucose uptake. To test this hypothesis, we propose three specific aims. Aim 1: we will analyze how HCV modulates SNX27-retromer function. Aim 2: we will evaluate how the interaction between HCV proteins and SNX27 regulates the surface level of GLUT1. Aim 3: we will explore how HCV regulates GLUT1 transport from endosome to plasma membrane and how HCV regulates glucose uptake. Our work will shed mechanistic insight on how HCV influences the glucose transport, and will provide a novel strategy for the treatment of HCV related diseases such as diabetes.

丙肝病毒（HCV）会引起宿主细胞葡萄糖转运功能缺陷，参与葡萄糖转运的重要蛋白之一——葡萄糖转运蛋白1（GLUT1）的细胞表面水平如何受HCV调控，尚有待研究。基于前期研究，本项目提出的科学假设是：丙肝病毒蛋白通过与SNX27相互作用，削弱SNX27与retromer重要组分VPS26的相互作用，从而影响SNX27-retromer货物之一GLUT1的运输，使得GLUT1在细胞表面的水平降低，进而抑制了细胞的葡萄糖摄取。本项目研究内容包括：（1）阐明HCV如何影响SNX27-retromer逆转运复合物功能；（2）分析HCV蛋白与SNX27的相互作用如何影响GLUT1的细胞表面水平；（3）探讨HCV如何调节GLUT1从内体到细胞质膜的运输及如何影响葡萄糖摄取。本项目将阐述HCV抑制葡萄糖吸收的新机制，为HCV导致的糖尿病等相关疾病的的治疗提供新的靶点和思路，具有重要的理论和潜在应用意义。

丙肝病毒HCV侵染导致胰岛素抵抗，而参与葡萄糖转运的GLUT1的细胞表面定位是否受HCV影响尚不清楚。SNX27-retromer是GLUT1从内体到细胞表面的主要运输途径，而这一途径是否被HCV利用仍有待研究。本项目基于病毒调节SNX27介导的内吞再循环这个学术思想，以SNX27-retromer的货物GLUT1为切入点，探讨HCV侵染对SNX27-retromer逆转运货物GLUT1在细胞表面的影响。我们发现HCV蛋白NS5A抑制SNX27-Vps26结合，进而抑制GLUT1从内体到细胞质膜的运输。通过本项目的实施，研究了HCV病毒蛋白与SNX27的相互作用的生物学意义，对于抗HCV感染的研究具有重要的理论价值，将为HCV的预防和治疗提供新的靶标，为丙型肝炎及其导致的糖尿病等相关疾病的治疗贡献一份力量。受丙肝病毒抑制GLUT1运输的启发，我们还开展了新冠病毒刺突蛋白S抑制SNX27货物GLUT1运输的研究，发现S不但能抑制SNX27与GLUT1的结合，还能够削弱SNX27与Vps26的结合，进而阻碍GLUT1从内体到细胞质膜的运输。S导致的GLUT1的减少可以解释部分新冠症状，如糖尿病、癫痫、运动失调和认知障碍等。