{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:49:43Z","timestamp":1793328583743,"version":"4.5.0"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272302"],"award-info":[{"award-number":["82272302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82241077"],"award-info":[{"award-number":["82241077"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070153"],"award-info":[{"award-number":["32070153"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82341084"],"award-info":[{"award-number":["82341084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"\u5317\u4eac\u5e02\u79d1\u5b66\u6280\u672f\u59d4\u5458\u4f1a | Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["Z220018"],"award-info":[{"award-number":["Z220018"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2300200-04"],"award-info":[{"award-number":["2021YFC2300200-04"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2305900"],"award-info":[{"award-number":["2023YFC2305900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tsinghua University Vanke Special Fund for Public Health and Health Discipline Development","award":["2022Z82WKJ013"],"award-info":[{"award-number":["2022Z82WKJ013"]}],"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"crossref"}]},{"name":"SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Tsinghua University Dushi Program","award":["20231080039"],"award-info":[{"award-number":["20231080039"]}],"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,20]]},"abstract":"<jats:p>The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism underlying this process has remained elusive. In this study, we performed a genome-wide CRISPR\/Cas9 screen, revealing that ZSWIM8 as the substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated STAT2 degradation. Genetic depletion of ZSWIM8 and CUL3 substantially impeded NS5-mediated STAT2 degradation. Biochemical analysis illuminated that NS5 enhances the interaction between STAT2 and the ZSWIM8\u2013CUL3 E3 ligase complex, thereby facilitating STAT2 ubiquitination. Moreover, ZSWIM8 knockout endowed A549 and Huh7 cells with partial resistance to ZIKV infection and protected cells from the cytopathic effects induced by ZIKV, which was attributed to the restoration of STAT2 levels and the activation of IFN signaling. Subsequent studies in a physiologically relevant model, utilizing human neural progenitor cells, demonstrated that ZSWIM8 depletion reduced ZIKV infection, resulting from enhanced IFN signaling attributed to the sustained levels of STAT2. Our findings shed light on the role of ZIKV NS5, serving as the scaffold protein, reprograms the ZSWIM8\u2013CUL3 E3 ligase complex to orchestrate STAT2 proteasome-dependent degradation, thereby facilitating evasion of IFN antiviral signaling. Our study provides unique insights into ZIKV\u2013host interactions and holds promise for the development of antivirals and prophylactic vaccines.<\/jats:p>","DOI":"10.1073\/pnas.2403235121","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T11:31:57Z","timestamp":1723721517000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":53,"title":["Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2"],"prefix":"10.1073","volume":"121","author":[{"given":"Wenlin","family":"Ren","sequence":"first","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-2783","authenticated-orcid":false,"given":"Chonglei","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-0222","authenticated-orcid":false,"given":"Xiaohui","family":"Ju","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Song","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Gong","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanxi Medical University-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, China"},{"name":"School of Management, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchun","family":"Fan","sequence":"additional","affiliation":[{"name":"Life Science Institute, Zhejiang University, Hangzhou 31008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4916-3412","authenticated-orcid":false,"given":"Jun","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ding","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Medicine, Tsinghua University, Beijing 100084, China"},{"name":"Shanxi Medical University-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-019-0421-x"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.01.004"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220028"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1578"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180628"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111680"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.025"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7871432"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90012-8"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3787"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3581"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.07.012"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508531102"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242388"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408824102"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.03.019"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02323-08"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02581-06"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.21.11166-11171.2002"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05732"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610977104"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.4.2425-2432.1994"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3527(03)59002-9"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60238-X"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0714-0"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.01.004"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1803406115"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.31919"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002780"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.05.009"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02188-08"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003265"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247005"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07901-8"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3951"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308676100"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1757"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.035"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep43613"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706987200"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc9359"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc9546"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.06.035"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-46503-6_12"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-8712-7"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203093"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07884"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-214957"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110557"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1601824"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6116"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.10.017"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.02.016"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0472-y"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-024-05768-8"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220005120"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw765"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2017.01.015"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01928"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00640-19"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01970-16"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.3390\/v10120712"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.06.007"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202357424"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-092818-015756"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.07.015"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15526"},{"key":"e_1_3_4_68_2","unstructured":"W. Ren RNA-Seq of A549 ZSWIM8 KO cell after ZIKV infection. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/sra\/PRJNA1141424. Deposited 29 July 2024."},{"key":"e_1_3_4_69_2","unstructured":"W. Ren RNA-Seq of NPCs ZSWIM8 KO cell after ZIKV infection. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/sra\/PRJNA1141425. Deposited 29 July 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2403235121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T11:32:49Z","timestamp":1723721569000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2403235121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,15]]},"references-count":69,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2024,8,20]]}},"alternative-id":["10.1073\/pnas.2403235121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2403235121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,15]]},"assertion":[{"value":"2024-02-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2403235121"}}