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Although many infections are asymptomatic, they can result in severe malnutrition and cognitive developmental impairments in pediatric populations.\n                      <jats:italic toggle=\"yes\">Giardia lamblia virus<\/jats:italic>\n                      (GLV) is a protozoan virus that specifically infects\n                      <jats:italic toggle=\"yes\">G. duodenalis<\/jats:italic>\n                      . This virus is characterized by its non-segmented, non-enveloped double-stranded RNA structure and contains essential proteins such as RNA-dependent RNA polymerase (RdRp) and capsid protein (GLVCP). While the interactions between RdRp and host proteins have been extensively investigated, the function of GLVCP remains largely unexplored. In this study, we employed various methodologies, including mass spectrometry, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC), to identify and characterize the interactions between GLVCP and host proteins of\n                      <jats:italic toggle=\"yes\">G. duodenalis<\/jats:italic>\n                      . Furthermore, we validated these interactions using CRISPR\/dCas9 gene editing and protein overexpression techniques. Our research revealed that an uncharacterized protein (UCP) containing a glycosyltransferase-stabilizing (Gtf2) domain interacts with GLVCP. Under GLV influence, UCP modulates GlcNAc-mediated O-glycosylation and regulates multiple proteins that are involved in different pathways, such as ABC transporters, Malate Dehydrogenase (MDH), and cathepsin B (CTSB), creating a favorable intracellular environment to viral survival. Our findings provide crucial insights into the GLV life cycle and underscore the intricate interactions between the parasite and the virus. These results could inform the development of novel strategies for controlling\n                      <jats:italic toggle=\"yes\">Giardia<\/jats:italic>\n                      infections and their associated diseases.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Our research has elucidated novel regulatory mechanisms between GLV and\n                        <jats:italic toggle=\"yes\">G. duodenalis<\/jats:italic>\n                        , highlighting the complex interactions involving GLVCP and a host protein (UCP, a characterized protein containing a Gtf2 domain). This interaction enhances host GlcNAc-mediated O-glycosylation, inhibits ATP transport, and promotes the cleavage of GLVCP by cathepsin B, thereby facilitating the uncoating and release of the viral genome. These findings deepen our understanding of the GLV life cycle and fill gaps in our knowledge of the intricate dynamics between protozoan viruses and their hosts, providing valuable insights for the development of innovative strategies to control\n                        <jats:italic toggle=\"yes\">Giardia<\/jats:italic>\n                        infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00883-25","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T13:00:26Z","timestamp":1758200426000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Identification of an uncharacterized protein as a novel regulator of\n                    <i>Giardia lamblia virus<\/i>\n                    (GLV) infection in\n                    <i>Giardia duodenalis<\/i>"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-7787","authenticated-orcid":true,"given":"Zhiteng","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04r17kf39","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Cao","sequence":"additional","affiliation":[{"name":"Jilin Academy of Animal Husbandry and Veterinary Medicine","place":["Changchun, 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