Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.

Cell systems Pub Date : 2024-12-18 Epub Date: 2024-12-09 DOI:10.1016/j.cels.2024.11.004
Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen
{"title":"Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.","authors":"Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen","doi":"10.1016/j.cels.2024.11.004","DOIUrl":null,"url":null,"abstract":"<p><p>Stimulator of interferon genes (STING) traffics across intracellular compartments to trigger innate responses. Mutations in factors regulating this process lead to inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen (OPS). Based on the subcellular localization of STING in 45 million cells, we defined 464 clusters of gene perturbations based on their cellular phenotypes. A secondary, higher-dimensional OPS identified 73 finer clusters. We show that the loss of the gene of unknown function C19orf25, which clustered with USE1, a protein involved in Golgi-to-endoplasmic reticulum (ER) transport, enhances STING signaling. Additionally, HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING Golgi exit. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches and provide a community resource for mining factors that impact STING trafficking and other cellular processes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"1264-1277.e8"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell systems","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cels.2024.11.004","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/9 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Stimulator of interferon genes (STING) traffics across intracellular compartments to trigger innate responses. Mutations in factors regulating this process lead to inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen (OPS). Based on the subcellular localization of STING in 45 million cells, we defined 464 clusters of gene perturbations based on their cellular phenotypes. A secondary, higher-dimensional OPS identified 73 finer clusters. We show that the loss of the gene of unknown function C19orf25, which clustered with USE1, a protein involved in Golgi-to-endoplasmic reticulum (ER) transport, enhances STING signaling. Additionally, HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING Golgi exit. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches and provide a community resource for mining factors that impact STING trafficking and other cellular processes.

全基因组光池筛选鉴定细胞内STING转运调节因子的分类和功能表征。
干扰素基因刺激因子(STING)通过细胞内隔室的交通来触发先天反应。调节这一过程的因子突变导致炎症性疾病。为了系统地确定涉及STING贩运的因素,我们进行了全基因组光学池筛选(OPS)。基于4500万个细胞中STING的亚细胞定位,我们根据其细胞表型定义了464个基因扰动簇。二级、高维OPS确定了73个更精细的集群。我们发现功能未知的基因C19orf25与参与高尔基到内质网(ER)转运的蛋白USE1聚集在一起,其缺失增强了STING信号传导。此外,啤酒花缺乏延迟了STING降解,从而增加了信号传导。同样,GARP/RIC1-RGP1的缺失通过延迟STING高尔基退出而增加了STING信号传导。我们的研究结果表明,基于高含量细胞成像的全基因组基因型-表型图谱优于其他筛选方法,并为挖掘影响STING运输和其他细胞过程的因素提供了社区资源。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信