Allosteric regulation of UBIAD1 trafficking from ER to Golgi revealed by chemical genetic screening

焦磷酸香叶基香叶基 内质网 焦磷酸法尼酯 内质网相关蛋白降解 高尔基体 苯丁酸酯 细胞生物学 生物 甾醇 生物化学 甲戊酸途径 亚氨基糖 化学 胆固醇 未折叠蛋白反应 还原酶 生物合成 内分泌学
作者
Dong-Jae Jun,Marc Schumacher,Youngah Jo,Rebecca A. Faulkner,Yangyang Yang,Jet Tsien,Tian Qin,Russell A. DeBose‐Boyd
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:122 (20)
标识
DOI:10.1073/pnas.2426532122
摘要

Schnyder corneal dystrophy (SCD) is a rare autosomal dominant condition characterized by the opacification of the cornea owing to the abnormal deposition of cholesterol. SCD-associated mutations have been identified in the gene encoding UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4 (MK-4). Beyond its enzymatic role, UBIAD1 serves as a key regulator of the endoplasmic reticulum (ER)-localized enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway that produces cholesterol and nonsterol isoprenoids such as GGpp and MK-4. Sterol-induced binding to UBIAD1 inhibits the sterol-accelerated ER-associated degradation (ERAD) of HMGCR to maintain the synthesis of nonsterol isoprenoids under conditions of cholesterol repletion. GGpp dissociates the HMGCR–UBIAD1 complex, triggering maximal ERAD of HMGCR and ER-to-Golgi translocation of UBIAD1. However, SCD-associated UBIAD1 resists this GGpp-induced dissociation and remains sequestered in the ER. ER retention of UBIAD1 leads to inhibition of HMGCR ERAD, promoting increased synthesis and accumulation of cholesterol. Here, chemical genetic screening was utilized to identify molecules that restored Golgi localization of SCD-associated UBIAD1 (N102S) and thereby relieve inhibition of HMGCR ERAD. We found that the chemotherapeutic tyrosine kinase inhibitor Apatinib stimulated ER-to-Golgi transport of both N102S and wild type UBIAD1. This effect required GGpp but was independent of Apatinib’s tyrosine kinase inhibition. Apatinib-mediated Golgi transport of UBIAD1 enhanced the ERAD of HMGCR. Photoaffinity labeling studies indicated that Apatinib binds directly to UBIAD1, suggesting that the drug allosterically activates GGpp-induced transport of UBIAD1 from the ER to the Golgi.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
yuqiubaba给yuqiubaba的求助进行了留言
刚刚
刚刚
111111aaa发布了新的文献求助10
刚刚
1秒前
杉杉发布了新的文献求助10
1秒前
1秒前
wenwen0666发布了新的文献求助20
3秒前
3秒前
5秒前
sunzy发布了新的文献求助100
5秒前
wanci应助黎23采纳,获得10
5秒前
imfangyu完成签到,获得积分10
5秒前
顺利的幻竹完成签到,获得积分10
6秒前
Tom完成签到,获得积分10
6秒前
开放身影发布了新的文献求助10
6秒前
6秒前
sunzy发布了新的文献求助10
7秒前
清秀送终发布了新的文献求助10
7秒前
ron发布了新的文献求助10
7秒前
干净寻冬发布了新的文献求助10
9秒前
9秒前
sunzy发布了新的文献求助20
10秒前
sunzy发布了新的文献求助10
12秒前
洛黎发布了新的文献求助10
13秒前
13秒前
13秒前
余健完成签到,获得积分10
14秒前
14秒前
15秒前
16秒前
hdskjahfi发布了新的文献求助10
16秒前
sunzy发布了新的文献求助10
16秒前
sunzy发布了新的文献求助10
16秒前
sunzy发布了新的文献求助30
16秒前
17秒前
17秒前
17秒前
17秒前
嘟噜完成签到 ,获得积分10
19秒前
19秒前
高分求助中
(应助此贴封号)【重要!!请各用户(尤其是新用户)详细阅读】【科研通的精品贴汇总】 10000
An Introduction to Foreign Language Learning and Teaching 750
China Pluperfect I: Epistemology of Past and Outside in Chinese Art 520
Matrix Methods in Data Mining and Pattern Recognition Second Edition 510
Cosmos as Art Object: Studies in Plato's Timaeus and Other Dialogues 500
What is the Future of Psychotherapy in Digital Age? Technology, AI Bots, and Psychotherapy after Covid 444
煤炭地下气化渗流燃烧方法的研究 400
热门求助领域 (近24小时)
化学 材料科学 医学 生物 纳米技术 工程类 有机化学 化学工程 生物化学 计算机科学 内科学 物理 复合材料 催化作用 细胞生物学 无机化学 光电子学 物理化学 电极 基因
热门帖子
关注 科研通微信公众号,转发送积分 7632447
求助须知:如何正确求助?哪些是违规求助? 9206828
关于积分的说明 19745793
捐赠科研通 7201797
什么是DOI,文献DOI怎么找? 3274824
关于科研通互助平台的介绍 2436740
邀请新用户注册赠送积分活动 2271501