[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-442752-105":59,"doc-detail-442752-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","npc1-trafficking-via-vps41-dependent-lamp-carriers-regulates-endosomal-cholesterol-homeostasis","NPC1 trafficking via VPS41-dependent LAMP carriers regulates endosomal cholesterol homeostasis","","Niemann–Pick type 1 and 2 proteins (NPC1 and NPC2) coordinate cholesterol export from late endosomes–lysosomes (LE/LY), and mutations cause Niemann–Pick type C disease, a progressive neurodegenerative lysosomal cholesterol storage disorder. To define NPC1 trafficking routes, genome-engineered HeLa cells expressing endogenous NPC1mNeon show NPC1 in the LE/LY compartment and in VPS41-containing membranes. VPS41 loss increases NPC1 and LAMP1, yet drives lysosomal cholesterol accumulation through a VPS41-dependent shift of NPC1 and LAMP1 from LE/LY to biosynthetic LAMP carriers.",{"@graph":69,"@context":122},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/npc1-trafficking-via-vps41-dependent-lamp-carriers-regulates-endosomal-cholesterol-homeostasis/442752/",{"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/npc1-trafficking-via-vps41-dependent-lamp-carriers-regulates-endosomal-cholesterol-homeostasis/442752.png","ImageObject",300,407,{"name":92,"@type":93},"jayni","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address about NPC1 trafficking?","Question",{"text":112,"@type":113},"The study addresses that the routes by which NPC1 reaches the late endosome–lysosome (LE/LY) compartment in mammalian cells are not fully understood, despite NPC1 being essential for cholesterol export.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do VPS41 and LAMP1 relate to NPC1 localization?",{"text":117,"@type":113},"The study shows NPC1 resides in the same membranes as VPS41, and loss of VPS41 increases NPC1 and LAMP1 abundance while causing cholesterol accumulation.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism explains the cholesterol changes when VPS41 is lost?",{"text":121,"@type":113},"Imaging and a VPS41-dependent recruitment assay indicate a localization shift: NPC1 and LAMP1 move from LE/LY to biosynthetic LAMP carriers, which deliver lysosome-destined cargo from the trans-Golgi network to LE/LY.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},442752,1790769868,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},3985747859343,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","RESEARCH ARTICLE  \nCELL BIOLOGY  \n OPEN ACCESS  \nNPC1 trafficking via VPS41-dependent LAMP carriers regulates endosomal cholesterol homeostasis  \nKlevis Ndoja, b,c,1, Matteo Tantuccid,1, Paolo Sanzad , Kristian Zubaka, b,c, Giorgia Marodina,e, Jenina Kingmaa, b,c , Felix Snijdera, b,c,  \nTineke Veenendaald , Daniel L. Koberf, Noam Zelcera, b,c,1,2, and Judith Klumpermand,1 Affiliations are included on p. 10.  \nEdited by Peter Tontonoz, University of California Los Angeles, Los Angeles, CA; received August 11, 2025; accepted November 26, 2025  \nThe Niemann-Pick type 1 and 2 proteins (NPC1 and NPC2) coordinate cholesterol egress from late endosomes-lysosomes (LE/LY). Proper folding, trafficking, and localization of both NPC proteins are essential for normal LE/LY cholesterol handling. Accordingly, mutations in NPC genes cause Niemann–Pick type C (NPC) disease, a progressive neurodegenerative lysosomal cholesterol storage disorder. The routes by which NPC1 reaches the LE/LY compartment in mammalian cells are not fully elucidated. Therefore, to interrogate NPC1 trafficking, we developed genome-engineered HeLa cells expressing endogenous NPC1mNeon. We demonstrate that endogenous NPC1 localizes to the LE/LY compartment and by using protein proximity-based approaches that NPC1 resides in the same membranes as Vacuolar Protein Sorting-associated protein 41 (VPS41), one of the two unique subunits of the homotypic fusion and vacuole protein sorting complex. Loss of VPS41 increases NPC1 and Lysosomal Associated Membrane Protein 1 (LAMP1) abundance. Paradoxically, this results in marked accumulation oflysosomal cholesterol and induction of sterol regulatory element-binding protein signaling. Mechanistically, using immuno-fluorescence and electron microscopy imaging in combination with aVPS41-dependent ectopic recruitment assay, we demonstrate that this is due to a shift in the localization of NPC1 and LAMP1 from LE/LY to biosynthetic vesicles called LAMP carriers. These vesicles have been recently described to transport lysosomal-destined cargo directly from the trans-Golgi (TGN) network to LE/LY. In conclusion, we identify NPC1 as a cargo for VPS41-dependent LAMP carriers that are instrumental for the delivery of NPC1 to LE/LY and maintaining cellular cholesterol homeostasis.  \nNPC1 | cholesterol metabolism | VPS41 | intracellular cholesterol transport | lysosomes  \nMammalian cells acquire exogenous cholesterol via the LDL–receptor pathway (1) . LDL is transported to late endosome/lysosome (LE/LY) compartments, where the coordinated action of Niemann-Pick type 1 and 2 (NPC1 and NPC2, respectively) promotes cholesterol egress (2–6) . Mutations in these NPC genes are the cause of Niemann–Pick type C (NPC) disease (OMIM\\# 257220), an autosomal recessive lysosomal cholesterol storage disorder characterized by progressive neurodegeneration (7–9) . Mutations in NPC1 account for the majority of cases (~95%), with the remaining ~5% attributed to mutations in NPC2 (8, 10, 11). At large, the mutations identified in NPC1 lead to misfolding and mistrafficking of the encoded protein, often resulting in its early endoplasmic reticulum-associated degradation or mislocalization (9, 12) . Nevertheless, many NPC1 mutant proteins retain their function, and delivery of even a small fraction of these mutant proteins to the LE/LY compartment is able to support cholesterol egress and overcome its accumulation (13–15), highlighting the importance of understanding the cellular itinerary that NPC1 follows.  \nTo fulfill their function in cellular cholesterol homeostasis, NPC proteins must reach the LE/LY compartments. While NPC2, a luminal soluble protein, is modified by the addition of a mannose-6-phosphate (M6P) group and relies on the M6P receptor (MPR) to reach LE/LY (16), the cellular itinerary followed by NPC1 is less clear. NPC1 is a 13 transmembrane domain protein that contains a C-terminal di-leucine motif (3, 9, 17) . This motif often acts as a sorting s","cbCaicTGNa6oshTC","https://ap.wps.com/l/cbCaicTGNa6oshTC","pdf",7214977,"English","# Abstract\n# Introduction\n## Cholesterol handling and NPC1/NPC2 function\n## Knowledge gap in NPC1 itinerary\n# Significance\n# Method overview (cell models and imaging)","[{\"question\":\"What problem does the study address about NPC1 trafficking?\",\"answer\":\"The study addresses that the routes by which NPC1 reaches the late endosome–lysosome (LE/LY) compartment in mammalian cells are not fully understood, despite NPC1 being essential for cholesterol export.\"},{\"question\":\"How do VPS41 and LAMP1 relate to NPC1 localization?\",\"answer\":\"The study shows NPC1 resides in the same membranes as VPS41, and loss of VPS41 increases NPC1 and LAMP1 abundance while causing cholesterol accumulation.\"},{\"question\":\"What mechanism explains the cholesterol changes when VPS41 is lost?\",\"answer\":\"Imaging and a VPS41-dependent recruitment assay indicate a localization shift: NPC1 and LAMP1 move from LE/LY to biosynthetic LAMP carriers, which deliver lysosome-destined cargo from the trans-Golgi network to LE/LY.\"}]","NPC1 trafficking via VPS41-dependent LAMP carriers regulates endosomal cholesterol homeostasis | PDF",1790701517,25]