[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-451551-105":59,"doc-detail-451551-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","regulation-of-sting-activation-by-phosphoinositide-and-cholesterol","Regulation of STING activation by phosphoinositide and cholesterol","","Stimulator of interferon genes (STING) is a key adaptor in the cytosolic DNA sensing innate immune pathway. STING activation depends on cyclic-GMP-AMP (cGAMP) produced by cGAS, which drives high-order oligomerization and trafficking from the endoplasmic reticulum to Golgi and post-Golgi vesicles. This work shows that specific phosphatidylinositol phosphates, especially PI(3,5)P2 and PI(4,5)P2, markedly enhance cGAMP-induced STING oligomerization, with PI(4)P contributing less.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/regulation-of-sting-activation-by-phosphoinositide-and-cholesterol/451551/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/regulation-of-sting-activation-by-phosphoinositide-and-cholesterol/451551.png","ImageObject",300,407,{"name":92,"@type":93},"eBook King","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-10","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What initiates STING activation in the cGAS/STING pathway?","Question",{"text":113,"@type":114},"DNA sensing activates cGAS, which produces cGAMP. cGAMP then binds STING and triggers the conformational changes required for activation.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do phosphoinositide phosphates influence STING activation?",{"text":118,"@type":114},"The study reports that PI(3,5)P2 and PI(4,5)P2 strongly enhance cGAMP-induced high-order oligomerization of STING, while PI(4)P has a lesser effect.",{"name":120,"@type":111,"acceptedAnswer":121},"What role do PIPs and cholesterol play according to the cryo-EM structures?",{"text":122,"@type":114},"The structures indicate that PIPs together with cholesterol bind at the interface between STING dimers, directly promoting high-order oligomerization and explaining preferences for different PIPs.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},451551,1790987901,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":41,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},962088006270,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.29.696921](https://doi.org/10.64898/2025.12.29.696921); this version posted December 29, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \nRegulation of STING activation by phosphoinositide and cholesterol  \nJie Li1 , Jay Xiaojun Tan4,5,6,7 , Zhijian J. Chen4,5,8 , Xuewu Zhang1,2,\\# & Xiao-chen Bai1,3,\\#  \n1 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA  \n2 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA  \n3 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA  \n4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390  \n5 Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390  \n6 Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219  \n7 Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219  \n8 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390  \n\\#Corresponding authors:  \n[xuewu.zhang@utsouthwestern.edu](xuewu.zhang@utsouthwestern.edu) (X.Z. ), [xiaochen.bai@utsouthwestern.edu](xiaochen.bai@utsouthwestern.edu) (X-C. B. ) .  \nbioRxiv preprint doi: [https://doi.org/10.64898/2025.12.29.696921](https://doi.org/10.64898/2025.12.29.696921); this version posted December 29, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \nAbstract  \nStimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA sensing innate immune pathway. STING is activated by cyclic-GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS) . cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to Golgi and post-Golgi vesicles are critical for STING activation. Recent studies have shown that phosphatidylinositol phosphates (PIPs) and cholesterol also play important roles in STING activation, but the underlying mechanisms remain unclear. Here, we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by PI(3,5)P2 and PI(4,5)P2 , and by PI(4)P to a less extent. Our cryo-EM structures reveal that PIPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PIPs. Mutational and biochemical analyses confirm the binding modes of PIPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING by specific lipids, which may underlie the role of intracellular compartment trafficking in dictating STING signaling.  \nMain  \nThe cGAS/STING pathway serves as a fundamental mechanism to detect cytosolic foreign DNA from invading pathogens , initiating innate immune responses against infections 1 . Activated by DNA, cGAS (cGAMP synthase) generates the second messenger 2’,3’-cyclic-GMPAMP (cGAMP), which binds to and activates the adaptor protein STING (Stimulator of Interferon Genes)2-5 . STING initiates multiple downstream pathways, including interferons, NF-κB, autophagy, and inflammasome, to eliminate pathogens. In addition, the cGAS/STING signaling pathway plays a pivotal role in anti-tumor immunity, due to activation of the pathway by fragmented DNA as a result of chromosomal instability in cancer cells and detection of ","cbCailjon7bUPBAY","https://ap.wps.com/l/cbCailjon7bUPBAY","pdf",16872535,"English","# Abstract\n## Background: STING in innate immune sensing\n## Mechanism: cGAMP-driven oligomerization and trafficking\n## Lipid regulation: phosphoinositides and cholesterol\n## Structural basis and validation by mutational/biochemical studies","[{\"question\":\"What initiates STING activation in the cGAS/STING pathway?\",\"answer\":\"DNA sensing activates cGAS, which produces cGAMP. cGAMP then binds STING and triggers the conformational changes required for activation.\"},{\"question\":\"How do phosphoinositide phosphates influence STING activation?\",\"answer\":\"The study reports that PI(3,5)P2 and PI(4,5)P2 strongly enhance cGAMP-induced high-order oligomerization of STING, while PI(4)P has a lesser effect.\"},{\"question\":\"What role do PIPs and cholesterol play according to the cryo-EM structures?\",\"answer\":\"The structures indicate that PIPs together with cholesterol bind at the interface between STING dimers, directly promoting high-order oligomerization and explaining preferences for different PIPs.\"}]","Regulation of STING activation by phosphoinositide and cholesterol | PDF",1790735406,76]