{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:26:44Z","timestamp":1787045204430,"version":"build-2736575974"},"reference-count":53,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100005407","name":"Food and Health Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["17123319"],"award-info":[{"award-number":["17123319"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004509","name":"Department of Health of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004509","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chan Yin Chuen Memorial Charitable Foundation"},{"name":"Chow Sin Lan Charity Fund Limited"},{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzhen","doi-asserted-by":"crossref","award":["SZSM201911014"],"award-info":[{"award-number":["SZSM201911014"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Zika virus (ZIKV) is an emerging flavivirus that may be associated with congenital anomalies in infected fetuses and severe neurological and genital tract complications in infected adults. Currently, antiviral treatments to revert these ZIKV-induced complications are lacking. ZIKV infection has recently been suggested to upregulate the host unfolded protein response, which may contribute to the congenital neurological anomalies. As an extension from these findings, we thoroughly investigated the ZIKV-induced unfolded protein response using a combination of the neuronal cell line, induced pluripotent stem cell-derived human neuronal stem and progenitor cells, and an interferon receptor-deficient A129 mouse model. Our results revealed a critical contribution of the inositol-requiring enzyme-1 (IRE1) arm of the unfolded protein response to ZIKV-induced neurological and testicular complications. Importantly, the inhibition of the IRE1 signaling pathway activation with KIRA6 (kinase-inhibiting RNAse attenuator 6), a selective small molecule IRE1 inhibitor that promotes cell survival, potently reverted the ZIKV-induced perturbations of the key gene expressions associated with neurogenesis and spermatogenesis in vitro and in vivo, highlighting the potential of IRE1 inhibition as a novel host-targeting antiviral strategy in combating against ZIKV-induced neurological and testicular pathologies.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00526","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T10:19:35Z","timestamp":1587723575000},"page":"1745-1758","source":"Crossref","is-referenced-by-count":11,"title":["Targeting the Inositol-Requiring Enzyme\u20111 Pathway\nEfficiently Reverts Zika Virus-Induced Neurogenesis and Spermatogenesis\nMarker Perturbations"],"prefix":"10.1021","volume":"6","author":[{"given":"Hin","family":"Chu","sequence":"first","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrence T. T.","family":"Yuen","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenn K. H.","family":"Chik","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuofeng","family":"Yuan","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Shuai","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijiao","family":"Zou","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Wang","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent K. M.","family":"Poon","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris C. S.","family":"Chan","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2948-3873","authenticated-orcid":true,"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Yin","sequence":"additional","affiliation":[{"name":"Hainan Medical University and The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative\nRegion, China, 999077"]},{"name":"Hainan Medical University , , , ,","place":["Haikou, Hainan, China, 571199"]},{"name":"Hainan Medical University , , , ,","place":["Haikou, Hainan, China, 571199"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin-Hang","family":"Kok","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-Yung","family":"Yuen","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"Hainan Medical University and The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative\nRegion, China, 999077"]},{"name":"Hainan Medical University , , , ,","place":["Haikou, Hainan, China, 571199"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong-Shenzhen Hospital , , , ,","place":["Shenzhen, Guangdong, China, 518053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6336-6657","authenticated-orcid":true,"given":"Jasper F. W.","family":"Chan","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"Hainan Medical University and The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative\nRegion, China, 999077"]},{"name":"Hainan Medical University , , , ,","place":["Haikou, Hainan, China, 571199"]},{"name":"The University of Hong Kong , , , ,","place":["Pokfulam, Hong Kong Special Administrative Region, China, 999077"]},{"name":"The University of Hong Kong-Shenzhen Hospital , , , ,","place":["Shenzhen, Guangdong, China, 518053"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,24]]},"reference":[{"issue":"3","key":"2026081722183886500_cit1","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1128\/CMR.00072-15","article-title":"Zika Virus","volume":"29","author":"Musso","year":"2016","journal-title":"Clin. 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Sci."},{"issue":"2","key":"2026081722183886500_cit18","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded\nprotein response: controlling cell fate decisions under ER stress\nand beyond","volume":"13","author":"Hetz","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"6","key":"2026081722183886500_cit19","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic interaction\nof BiP and ER stress transducers in the unfolded-protein response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"issue":"47","key":"2026081722183886500_cit20","doi-asserted-by":"publisher","first-page":"34525","DOI":"10.1074\/jbc.M704300200","article-title":"The role of brain-derived\nneurotrophic factor (BDNF)-induced XBP1 splicing during brain development","volume":"282","author":"Hayashi","year":"2007","journal-title":"J. Biol. Chem."},{"issue":"5","key":"2026081722183886500_cit21","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.devcel.2015.11.005","article-title":"A Dynamic\nUnfolded Protein Response Contributes to the Control of Cortical Neurogenesis","volume":"35","author":"Laguesse","year":"2015","journal-title":"Dev. Cell"},{"issue":"1","key":"2026081722183886500_cit22","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41593-017-0038-4","article-title":"Stress-induced\nunfolded protein response contributes to Zika virus-associated microcephaly","volume":"21","author":"Gladwyn-Ng","year":"2018","journal-title":"Nat. Neurosci."},{"issue":"7","key":"2026081722183886500_cit23","doi-asserted-by":"publisher","first-page":"4679","DOI":"10.1074\/jbc.M111.284695","article-title":"Influenza A viral\nreplication is blocked by inhibition of the inositol-requiring enzyme\n1 (IRE1) stress pathway","volume":"287","author":"Hassan","year":"2012","journal-title":"J. Biol. 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Mol.\nGenet."},{"issue":"22","key":"2026081722183886500_cit33","doi-asserted-by":"publisher","first-page":"5928","DOI":"10.1093\/hmg\/ddu317","article-title":"Ubiquitin-specific protease-14 reduces\ncellular aggregates and protects against mutant huntingtin-induced\ncell degeneration: involvement of the proteasome and ER stress-activated\nkinase IRE1alpha","volume":"23","author":"Hyrskyluoto","year":"2014","journal-title":"Hum. Mol. 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Invest."},{"issue":"1","key":"2026081722183886500_cit37","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41426-018-0080-7","article-title":"Human testicular organoid system\nas a novel tool to study Zika virus pathogenesis","volume":"7","author":"Strange","year":"2018","journal-title":"Emerging Microbes Infect."},{"issue":"2","key":"2026081722183886500_cit38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006854","article-title":"Ebselen alleviates\ntesticular pathology\nin mice with Zika virus infection and prevents its sexual transmission","volume":"14","author":"Simanjuntak","year":"2018","journal-title":"PLoS Pathog."},{"issue":"2","key":"2026081722183886500_cit39","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602899","article-title":"Zika virus causes testicular atrophy","volume":"3","author":"Uraki","year":"2017","journal-title":"Sci. Adv."},{"issue":"3","key":"2026081722183886500_cit40","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.cell.2014.07.002","article-title":"Allosteric\ninhibition of the IRE1alpha RNase preserves cell viability and function\nduring endoplasmic reticulum stress","volume":"158","author":"Ghosh","year":"2014","journal-title":"Cell"},{"issue":"1","key":"2026081722183886500_cit41","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41426-018-0096-z","article-title":"ZIKA virus infection causes persistent chorioretinal\nlesions","volume":"7","author":"Manangeeswaran","year":"2018","journal-title":"Emerging Microbes Infect."},{"issue":"1","key":"2026081722183886500_cit42","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1083\/jcb.200406136","article-title":"XBP1: a link between\nthe unfolded protein response, lipid biosynthesis, and biogenesis\nof the endoplasmic reticulum","volume":"167","author":"Sriburi","year":"2004","journal-title":"J. Cell Biol."},{"issue":"24","key":"2026081722183886500_cit43","doi-asserted-by":"publisher","first-page":"11776","DOI":"10.1073\/pnas.1814480116","article-title":"Coupling of COPII vesicle trafficking\nto nutrient availability by the IRE1alpha-XBP1s axis","volume":"116","author":"Liu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081722183886500_cit44","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2016.99","article-title":"Differential cell\nline susceptibility\nto the emerging Zika virus: implications for disease pathogenesis,\nnon-vector-borne human transmission and animal reservoirs","volume":"5","author":"Chan","year":"2016","journal-title":"Emerging Microbes Infect."},{"key":"2026081722183886500_cit45","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.ebiom.2016.11.017","article-title":"Zika Virus\nInfection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated\nInfection with Multi-organ Involvement Including Orchitis Effectively\nTreated by Recombinant Type I Interferons","volume":"14","author":"Chan","year":"2016","journal-title":"EBioMedicine"},{"issue":"30","key":"2026081722183886500_cit46","doi-asserted-by":"publisher","first-page":"11709","DOI":"10.1074\/jbc.RA118.001897","article-title":"Middle\nEast respiratory syndrome coronavirus and bat coronavirus HKU9 both\ncan utilize GRP78 for attachment onto host cells","volume":"293","author":"Chu","year":"2018","journal-title":"J. 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