{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Interferon‐induced transmembrane protein 3 (IFITM3) is a critical effector of the innate antiviral response that restricts a broad range of viruses by acting at early stages of infection. In vivo and in vitro studies demonstrate that IFITM3 is essential for host defense against influenza A virus, as loss or reduced function (e.g. by the rs12252‐C allele) leads to increased viral replication, severe pneumonia, and enhanced mortality."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, IFITM3 restricts other pathogenic viruses—including HIV‐1, Zika virus, and SARS‐CoV‐2—by interfering with virus–cell fusion events. Mechanistically, IFITM3 modulates membrane properties by blocking the transition from hemifusion to full fusion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and by altering intracellular cholesterol homeostasis through disruption of VAPA–OSBP interactions, thereby impeding viral entry."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In HIV‐1–infected cells, IFITM3 can be incorporated into nascent virions to further inhibit the entry of progeny virus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and its broad antiviral function is also observed in the context of Zika virus infection, where it prevents virus‐induced cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " The antiviral efficiency of IFITM3 is tightly regulated by post‐translational modifications, including S‐palmitoylation, ubiquitination, and phosphorylation, which control its intracellular trafficking and localization to endolysosomal compartments, the primary sites of viral fusion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " In addition, the amphipathic helix region of IFITM3 is critical for its antiviral action against SARS‐CoV‐2, and mutations affecting endocytosis signals can transform its function from restriction to enhancement of infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " IFITM3 is also expressed by specialized immune cells, such as lung-resident memory CD8⁺ T cells, where its persistent expression affords protection against secondary viral challenges by preventing cell infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Finally, recent evidence suggests that IFITM3 can be exported in exosomes, thus mediating intercellular transfer of antiviral activity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", underscoring its potential as a target for antiviral therapeutic strategies. Collectively, these studies emphasize that the antiviral functions of IFITM3—ranging from direct inhibition of viral entry and fusion to modulation by genetic and post‐translational mechanisms—are central to maintaining the resistance of both individual cells and the organism to diverse viral pathogens."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Aaron R Everitt, Simon Clare, Thomas Pertel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IFITM3 restricts the morbidity and mortality associated with influenza."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature10921"}], "href": "https://doi.org/10.1038/nature10921"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22446628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22446628"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhongfang Wang, Anli Zhang, Yanmin Wan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1321748111"}], "href": "https://doi.org/10.1073/pnas.1321748111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24367104"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24367104"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yong-Hong Zhang, Yan Zhao, Ning Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms2433"}], "href": "https://doi.org/10.1038/ncomms2433"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23361009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23361009"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Tanay M Desai, Mariana Marin, Christopher R Chin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IFITM3 restricts influenza A virus entry by blocking the formation of fusion pores following virus-endosome hemifusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1004048"}], "href": "https://doi.org/10.1371/journal.ppat.1004048"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24699674"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24699674"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Samad Amini-Bavil-Olyaee, Youn Jung Choi, Jun Han Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2013.03.006"}], "href": "https://doi.org/10.1016/j.chom.2013.03.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23601107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23601107"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Alex A Compton, Timothée Bruel, Françoise Porrot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IFITM proteins incorporated into HIV-1 virions impair viral fusion and spread."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2014.11.001"}], "href": "https://doi.org/10.1016/j.chom.2014.11.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25464829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25464829"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "George Savidis, Jill M Perreira, Jocelyn M Portmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The IFITMs Inhibit Zika Virus Replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.05.074"}], "href": "https://doi.org/10.1016/j.celrep.2016.05.074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27268505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27268505"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jacob S Yount, Roos A Karssemeijer, Howard C Hang "}, {"type": "b", "children": [{"type": "t", "text": "S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.362095"}], "href": "https://doi.org/10.1074/jbc.M112.362095"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22511783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22511783"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Sinu P John, Christopher R Chin, Jill M Perreira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.00481-13"}], "href": "https://doi.org/10.1128/JVI.00481-13"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23658454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23658454"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Nicholas M Chesarino, Temet M McMichael, Jocelyn C Hach, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of the antiviral protein interferon-inducible transmembrane protein 3 (IFITM3) dually regulates its endocytosis and ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.557694"}], "href": "https://doi.org/10.1074/jbc.M114.557694"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24627473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24627473"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Guoli Shi, Adam D Kenney, Elena Kudryashova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Opposing activities of IFITM proteins in SARS-CoV-2 infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.2020106501"}], "href": "https://doi.org/10.15252/embj.2020106501"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33270927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33270927"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Linda M Wakim, Nishma Gupta, Justine D Mintern, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced survival of lung tissue-resident memory CD8⁺ T cells during infection with influenza virus due to selective expression of IFITM3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.2525"}], "href": "https://doi.org/10.1038/ni.2525"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23354485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23354485"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xun Zhu, Zhenjian He, Jie Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IFITM3-containing exosome as a novel mediator for anti-viral response in dengue virus infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Microbiol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cmi.12339"}], "href": "https://doi.org/10.1111/cmi.12339"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25131332"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25131332"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jennifer Lu, Qinghua Pan, Liwei Rong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The IFITM proteins inhibit HIV-1 infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.01531-10"}], "href": "https://doi.org/10.1128/JVI.01531-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21177806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21177806"}]}]}]}