中文版 | English
题名

靶向 DHODH 介导的嘧啶合成调控线粒体动 态激活抗病毒天然免疫机制

其他题名
Targeting DHODH-mediated pyrimidine synthesis activates antiviral immune response by regulating mitochondrial dynamics
姓名
姓名拼音
WANG Chen
学号
12133155
学位类型
硕士
学位专业
0710 生物学
学科门类/专业学位类别
07 理学
导师
王艺瑾
导师单位
药理学系
论文答辩日期
2024-05-09
论文提交日期
2024-07-01
学位授予单位
南方科技大学
学位授予地点
深圳
摘要

DHODH 是嘧啶生物合成关键酶,靶向 DHODH 通过影响细胞内核苷 酸合成和促进天然免疫激活发挥广谱抗病毒功能。本文旨在探究靶向 DHODH 介导的嘧啶合成调控抗病毒天然免疫的机制。我们发现 DHODH 抑制剂布喹那钠 (Brequinar, BQR) 激活干扰素刺激基因 (Interferon Stimulate Genes, ISGs) 表达。Uridine 是尿嘧啶和核糖构成的小分子代谢物, 用于补救细胞内的嘧啶合成。Uridine 可以抑制 BQR 激活的 ISGs,提示靶 向 DHODH 是通过影响嘧啶合成激活天然免疫。为探究靶向 DHODH 介导 的嘧啶合成是否通过 RNA 病毒激活天然免疫所需的 RIG-I/MDA5 受体,我 们敲除 RIG-I 和 MDA5,发现 BQR 对 ISGs 的激活被显著抑制,提示 BQR 激活 ISGs 依赖于 RIG-I 和 MDA5。DHODH 定位于线粒体内膜,我们发现 BQR 处理后细胞发生线粒体融合,而 uridine 共同处理可以减少线粒体融合 现,恢复线粒体正常形态。通过检测线粒体动态调控相关蛋白 OPA1、 MFN1、MFN2、FIS1、DRP1 发现,BQR 处理后长 OPA1 没有明显差异, 但是短 OPA1 的表达增加,提示短 OPA1 可能是线粒体融合介导的靶向 DHODH 所激活抗病毒天然免疫的关键因子。以上结果为探索靶向 DHODH 介导的嘧啶合成激活天然免疫提供了新思路,同时也建立起了线粒体动态、 嘧啶合成抑制及激活天然免疫的联系。

关键词
语种
英语
培养类别
独立培养
入学年份
2021
学位授予年份
2024-07
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王晨. 靶向 DHODH 介导的嘧啶合成调控线粒体动 态激活抗病毒天然免疫机制[D]. 深圳. 南方科技大学,2024.
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