{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:55Z","timestamp":1792785235585,"version":"4.5.0"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"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":["82341077"],"award-info":[{"award-number":["82341077"]}],"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":["32270797"],"award-info":[{"award-number":["32270797"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pearl River Talent Recruitment Program","award":["2023CX10Y071"],"award-info":[{"award-number":["2023CX10Y071"]}]},{"name":"R&D Program of Guangzhou National Laboratory","award":["GZNL2024A01014"],"award-info":[{"award-number":["GZNL2024A01014"]}],"id":[{"id":"https:\/\/ror.org\/03ybmxt82","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":[[2026,10,6]]},"abstract":"<jats:p>Many medically important viruses, including HIV\u22121 and severe acute respiratory syndrome coronavirus 2, utilize programmed \u22121 ribosomal frameshifting (\u22121 PRF) to synthesize certain proteins essential for the viral life cycle. Shiftless (SHFL) is an interferon-simulated, zinc finger-containing protein that restricts \u22121 PRF and viral infection. However, its regulatory spectrum and mechanism remain largely unclear. Here, we showed that SHFL orthologs potently suppress a wide variety of viral and cellular \u22121 PRF, and that this activity is evolutionarily conserved in mammals. Notably, mammalian SHFL proteins contain three zinc finger domains and inhibit \u22121 PRF in a zinc ion- and zinc finger-dependent manner. Structural and biochemical analyses revealed that SHFL is an autoinhibited protein, in which the C-terminal domain (CTD) serves as the principal functional module through mediating RNA binding, homotypic oligomerization, and ribosomal interaction, whereas the N-terminal domain (NTD) negatively regulates CTD activity through intramolecular interaction. Either zinc binding to the three zinc fingers or genetical disruption of the NTD\u2013CTD interaction by point mutagenesis likely drives conformational rearrangement that relieves autoinhibition and converts SHFL into an active conformation. Together, these findings uncover a previously unrecognized mechanism of zinc ion- and zinc finger-mediated allosteric activation of SHFL, providing a molecular framework for broad-spectrum suppression of viral and cellular \u22121 PRF.<\/jats:p>","DOI":"10.1073\/pnas.2608087123","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:02:56Z","timestamp":1790622176000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Zinc mediates the allosteric activation of Shiftless to suppress programmed \u22121 ribosomal frameshifting"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2442-0392","authenticated-orcid":false,"given":"Shi-Ting","family":"He","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangzhou National Laboratory, Guangzhou","place":["Guangdong, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Zheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangzhou National Laboratory, Guangzhou","place":["Guangdong, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhong","family":"Ying","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00z0j0d77","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangzhou National Laboratory, Guangzhou","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8200-1600","authenticated-orcid":false,"given":"Qiman","family":"Fang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00zat6v61","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Basic Medical Sciences, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8832-6307","authenticated-orcid":false,"given":"Xiujuan","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00zat6v61","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Basic Medical Sciences, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7081-4060","authenticated-orcid":false,"given":"Runxi","family":"Luo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00zat6v61","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Basic Medical Sciences, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4131-2916","authenticated-orcid":false,"given":"Xinqi","family":"Zhu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00z0j0d77","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumin","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00z0j0d77","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzheng","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease Shenzhen Third People\u2019s Hospital, and Department of Biochemistry, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7967-2755","authenticated-orcid":false,"given":"Xiaonan","family":"Dong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangzhou National Laboratory, Guangzhou","place":["Guangdong, China"]},{"id":[{"id":"https:\/\/ror.org\/00z0j0d77","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Infection and Health, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060815-014818"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.53.3.273-298.1989"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.26.120192.000333"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-012120-101548"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-111821-120646"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2416054"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/331280a0"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90124-4"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/18.15.4535"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.65.6.2910-2920.1991"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01315421"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00077-11"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.1.174"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.22.10612-10622.2001"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-72-8-1819"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1094\/MPMI-6-444"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1998.9358"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355838200000510"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-5-108"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01979-09"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102932108"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03511-5"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.030"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005357"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01606-16"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00373-19"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-00846-z"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12250-021-00423-6"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/v14071454"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15122296"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adw7471"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01864-25"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355838298971576"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2004.11.038"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13429"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04627-y"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/v14020177"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023051118"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27431-0"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15582"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz503"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.19.4079"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki299"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msae154"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511629200"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13071230"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/v16040583"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2178"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b00753"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.7b05140"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0321081"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC120.013449"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02480-09"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/v5010279"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112076"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112987"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.085621"},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202501727","article-title":"Human Schlafen 14 cleavage of short double-stranded RNAs underpins its antiviral activity","volume":"12","author":"Li M.","year":"2025","unstructured":"M. Li , Human Schlafen 14 cleavage of short double-stranded RNAs underpins its antiviral activity. Adv. Sci. (Weinh) 12, e01727 (2025).","journal-title":"Adv. Sci. (Weinh)"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.03.047"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29030"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114343"},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","DOI":"10.1128\/spectrum.01284-23","article-title":"Mouse liver-expressed shiftless is an evolutionarily conserved antiviral effector restricting human and murine hepaciviruses","volume":"11","author":"Zhang Y.","year":"2023","unstructured":"Y. Zhang , Mouse liver-expressed shiftless is an evolutionarily conserved antiviral effector restricting human and murine hepaciviruses. Microbiol. Spectr. 11, e0128423 (2023).","journal-title":"Microbiol. Spectr."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2608087123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:04:09Z","timestamp":1790622249000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2608087123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":63,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,10,6]]}},"alternative-id":["10.1073\/pnas.2608087123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2608087123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"assertion":[{"value":"2026-03-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2608087123"}}