[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-407525-105":59,"doc-detail-407525-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","march-to-combat-zika-virus-infection","MARCH to combat Zika virus infection","","MARCH proteins (MARCH1-11) are E3 ubiquitin ligases that regulate trafficking and levels of cellular and viral proteins, shaping antiviral outcomes via ubiquitin-dependent protein degradation or retention. Zhang et al. identify MARCH2 and MARCH3 as key negative regulators of the Zika entry receptor TIM-1 by promoting K48-linked polyubiquitination on distinct lysines, driving proteasomal degradation. Loss of MARCH2/3 elevates TIM-1 and increases ZIKV (and dengue) infection across cell lines, while TIM-1 ubiquitination-resistant mutants worsen infectivity, and knockout mice show higher viral loads.",{"@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":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/march-to-combat-zika-virus-infection/407525/",{"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/march-to-combat-zika-virus-infection/407525.png","ImageObject",300,407,{"name":92,"@type":93},"Sophia Brooks","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Which MARCH proteins regulate the Zika entry receptor TIM-1?","Question",{"text":112,"@type":113},"MARCH2 and MARCH3 significantly reduce TIM-1 levels and act as negative regulators of TIM-1 under physiological conditions.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do MARCH2 and MARCH3 control TIM-1 at the molecular level?",{"text":117,"@type":113},"They interact with TIM-1 and promote K48-linked polyubiquitination: MARCH2 targets lysine 338, while MARCH3 targets lysine 346, leading to proteasomal degradation.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the effect of MARCH2/3 loss on Zika virus infection in cells and animals?",{"text":121,"@type":113},"Knocking out MARCH2 or MARCH3 increases TIM-1 and elevates ZIKV infection in multiple cell lines; in mice, MARCH2/3 knockout causes higher viral loads and weight loss, especially in double knockouts.","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},407525,1790789651,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":81,"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":39,"preview_page_count":4},962084925636,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","[www.nature.com/cmi](www.nature.com/cmi)  \nCOMMENT OPEN   \nMARCH to combat Zika virus infection  \nUpendra Pradeep Lambe1 and Rohit K. Jangra 1 ✉  \n© The Author(s) 2025  \nCellular & Molecular Immunology (2026) 23:114–116; [https://doi.org/10.1038/s41423-025-01359-7](https://doi.org/10.1038/s41423-025-01359-7)  \nThe ubiquitination of proteins, followed by their degradation via the proteasome or autophagosome, is a key mechanism for the posttranslational regulation of proteins in cells. The specificity of this process is primarily dictated by the E3 ubiquitin ligases, which are classified into three main types: the really interesting new gene (RING), the RING-between-RING (RBR), and the homologous to the human papillomavirus E6 protein-associated protein (E6-AP) carboxyl terminus (HECT) . Among the RING-type E3 ubiquitin ligases are the membrane-associated or membrane-proximal RING-CH (MARCH) proteins, which regulate the trafficking and levels of cellular and viral proteins, including immune receptors, innate immune response proteins, and viral glycoproteins [1] . Eleven MARCH proteins, named MARCH1-11, are encoded in the human genome, and some of them (primarily MARCH8 along with MARCH1 and MARCH2) have been implicated in antiviral defense against RNA viruses such as human immunodeficiency virus (HIV- 1), influenza virus, Ebola virus, SARS-CoV-2, and respiratory syncytial virus (RSV) [2] . MARCH proteins usually exert their antiviral effects by decreasing the incorporation of viral glycoproteins into virions through ubiquitin- and cytoplasmic taildependent lysosomal degradation or ubiquitin- and cytoplasmic tail-independent retention in endosomes and the trans-Golgi network and/or blockade of glycoprotein maturation (Fig. 1) . MARCH proteins can also restrict virus infection by selectively degrading nonenvelope viral proteins. Zhang et al. described a novel way by which MARCH proteins can inhibit virus infection: by downregulating the host receptor T-cell immunoglobulin and mucin domain-1 (TIM-1), which facilitates Zika virus (ZIKV) entry, to block infection (Fig. 1) [3] .  \nTo identify the MARCH protein(s) capable of downregulating TIM- 1 expression, the authors coexpressed all 11 MARCH proteins, each with TIM-1, in human cells. MARCH2 and MARCH3 proteins significantly reduce TIM-1 levels. By knocking out MARCH2 and MARCH3 separately or together in mice, they demonstrated that MARCH2 and MARCH3 function as negative regulators of TIM-1 under physiological conditions. Although they could each downregulate TIM-1 separately, double knockout mice presented a much greater reduction in TIM-1 levels, highlighting their redundant roles, which makes sense given their close phylogenetic relationship and cellular localization. Coimmunoprecipitation experiments revealed that both MARCH2 and MARCH3 interact with the TIM-1 receptor to promote K48-linked polyubiquitination of TIM-1 . Detailed mutagenesis experiments revealed that MARCH2 causes polyubiquitination at lysine 338 of TIM-1, whereas MARCH3 targets lysine 346, leading to proteasomal degradation of TIM-1 . Complementary overexpression experiments verified the specific involvement of MARCH2/3 in TIM-1 degradation. In contrast, MARCH2 and MARCH3 did not have  \nany downregulatory effects on the other cellular receptor, CXCR7 . Therefore, MARCH2/3 control the steady-state levels of TIM-1 both in cell culture and in vivo.  \nCell culture experiments demonstrated that MARCH2/3-mediated downregulation of TIM-1 decreased ZIKV infection. Knocking out either MARCH2 or MARCH3 increased TIM-1 levels, resulting in a moderate increase in ZIKV infection. Furthermore, knocking out both MARCH2 and MARCH3 strongly reduced ZIKV infection in wild-type cells, but this effect was not detected in TIM- 1 knockout cells. This pattern was consistently observed across various cell lines, including hepatic (Huh7), placental (BeWo), and neuronal (U87, U251) cells. Dengue virus (DENV), another flavivirus that uses the TIM-1","cbCaikNBKdt5Mmon","https://ap.wps.com/l/cbCaikNBKdt5Mmon","pdf",870211,"English","# Background\n## E3 ubiquitin ligases and MARCH proteins\n# Identification of the TIM-1 regulators\n## Coexpression and knockout findings\n## Polyubiquitination targets and degradation mechanism\n# Functional impact on viral infection\n## ZIKV and dengue specificity\n## TIM-1 mutant validation\n# In vivo validation\n## Mouse infection outcomes\n## Species-specific lysine recognition\n# Implications and future questions","[{\"question\":\"Which MARCH proteins regulate the Zika entry receptor TIM-1?\",\"answer\":\"MARCH2 and MARCH3 significantly reduce TIM-1 levels and act as negative regulators of TIM-1 under physiological conditions.\"},{\"question\":\"How do MARCH2 and MARCH3 control TIM-1 at the molecular level?\",\"answer\":\"They interact with TIM-1 and promote K48-linked polyubiquitination: MARCH2 targets lysine 338, while MARCH3 targets lysine 346, leading to proteasomal degradation.\"},{\"question\":\"What is the effect of MARCH2/3 loss on Zika virus infection in cells and animals?\",\"answer\":\"Knocking out MARCH2 or MARCH3 increases TIM-1 and elevates ZIKV infection in multiple cell lines; in mice, MARCH2/3 knockout causes higher viral loads and weight loss, especially in double knockouts.\"}]","MARCH to combat Zika virus infection | PDF",1790574435]