AbstractFour endemic seasonal human coronaviruses causing common colds, HKU1, 229E, NL63 and OC43 circulate worldwide1. After binding to cellular receptors, coronavirus spike proteins are primed for fusion by transmembrane-serine protease 2 (TMPRSS2) or endosomal cathepsins2-9. NL63 uses angiotensin-converting enzyme 2 (ACE2) as a receptor10, whereas 229E uses human aminopeptidase-N11.

摘要导致感冒的四种地方性季节性人类冠状病毒HKU1229E，NL63和OC43在世界范围内传播1。在与细胞受体结合后，冠状病毒刺突蛋白被跨膜丝氨酸蛋白酶2（TMPRSS2）或内体组织蛋白酶2-9引发融合。NL63使用血管紧张素转换酶2（ACE2）作为受体10，而229E使用人氨肽酶-N11。

HKU1 and OC43 spikes bind cells through 9-O40 acelytated sialic acid but their protein receptors remain unknown12. Here, we show that TMPRSS2 is a functional receptor for HKU1. TMPRSS2 triggers HKU1 spike-mediated cell42 cell fusion and pseudovirus infection. Catalytically inactive TMPRSS2 mutants do not cleave HKU1 spike but allow pseudovirus infection.

HKU1和OC43峰值通过9-O40乙酰化唾液酸结合细胞，但它们的蛋白质受体仍然未知12。在这里，我们显示TMPRSS2是HKU1的功能性受体。TMPRSS2触发HKU1刺突介导的细胞42细胞融合和假病毒感染。催化失活的TMPRSS2突变体不切割HKU1刺突，但允许假病毒感染。

Furthermore, TMPRSS2 binds with high affinity to the HKU1 receptor binding domain (RBD) (Kd 334 and 137 nM for HKU1A and HKU1B genotypes) but not to SARS-CoV-2. Conserved amino acids within HKU1 RBD are essential for binding to TMPRSS2 and pseudovirus infection. Newly designed anti-TMPRSS2 nanobodies potently inhibit HKU1 spike attachment to TMPRSS2, fusion and pseudovirus infection.

此外，TMPRSS2以高亲和力结合HKU1受体结合结构域（RBD）（HKU1A和HKU1B基因型的Kd 334和137nM），但不结合SARS-CoV-2。HKU1 RBD中的保守氨基酸对于结合TMPRSS2和假病毒感染至关重要。新设计的抗TMPRSS2纳米抗体有效抑制HKU1刺突附着于TMPRSS2，融合和假病毒感染。

The nanobodies also reduce infection of primary human bronchial cells by an authentic HKU-1 virus. Our findings illustrate the various evolution strategies of coronaviruses, which use TMPRSS2 to either directly bind to target cells or to prime their spike for membrane fusion and entry..

纳米抗体还可以减少真正的HKU-1病毒对原代人支气管细胞的感染。我们的研究结果说明了冠状病毒的各种进化策略，这些策略使用TMPRSS2直接与靶细胞结合或引发其尖峰进行膜融合和进入。。

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Author informationAuthor notesThese authors contributed equally: Julian Buchrieser, Olivier SchwartzAuthors and AffiliationsVirus & Immunity Unit, Institut Pasteur, Université de Paris Cité, Paris, FranceNell Saunders, Maaran Michael Rajah, Jeanne Postal, Francoise Porrot, Florence Guivel-Benhassine, Augustin Martin, Ludivine Grzelak, Hunter Hoover-Watson, Julian Buchrieser & Olivier SchwartzStructural Virology Unit, Institut Pasteur, Université de Paris Cité, Paris, FranceIgnacio Fernandez, Rischa Maya Oktavia, Annalisa Meola, Olivia Ahouzi & Felix ReyHumoral Immunology Unit, Institut Pasteur, Université de Paris Cité, Paris, FranceCyril Planchais & Hugo MouquetPathogenesis of Vascular Infections Unit, Institut Pasteur, INSERM, Paris, FranceVincent MichelNanoimaging core, Institut Pasteur, Université de Paris Cité, Paris, FranceEduard Baquero SalazarPasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris Cité, Paris, FranceCatherine BlancAntibody Engineering Platform, C2RT, Institut Pasteur, Université de Paris Cité, Paris, FranceGaëlle Chauveau-Le Friec, Véronique Meriaux & Pierre LafayeG5 Evolutionary Genomics of RNA Viruses, Institut Pasteur, Paris, FranceMatthieu Prot, Deborah Delaune & Etienne Simon-LorièreInstitut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, FranceDeborah DelauneDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC, Molecular Diagnostic Unit, University of Amsterdam, Amsterdam, NetherlandsMarion CornelissenAmsterdam Institute for Infection and Immunity, Amsterdam, The NetherlandsMarion Cornelissen, Martin Deijs & Lia van der HoekDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC, Laboratory of Experimental Virology, University of Amsterdam, Amsterdam, NetherlandsMartin Deijs & L.

作者信息作者注作者同等贡献：Julian Buchrieser，Olivier SchwartzAuthors and AffiliationsVirus＆Immunity Unit，Institut Pasteur，UniversitédeParisCité，Paris，FranceNell Saunders，Maaran Michael Rajah，Jeanne Postal，Francoise Porrot，Florence Guivel Benhassine，Augustin Martin，Ludivine Grzelak，Hunter-Hoover Watson，Julian Buchrieser＆Olivier SchwartzStructural Virology Unit，Institut Pasteur，Universitéde Paris-Cité，Paris，FranceIgnacio Fernandez，Rischa Maya Oktavia，Annalisa Meola，Olivia Ahouzi＆Felix ReyHumoral Immunology Unit，Institut Pasteur，Universitéde Paris-Cité，Paris，FranceCyril Planchais＆Hugo MouquetPathogenesis of Vascular Infections Unit，Institut Pasteur，Ins，巴黎，弗朗西文森特·米歇尔纳米成像核心，巴斯德研究所，巴黎西特大学，法国爱德华·巴克罗·萨拉扎巴斯德·特拉维特斯联合实验室，巴斯德研究所，巴黎西特大学，巴黎，弗朗西塞琳·布兰卡抗体工程平台，C2RT，巴斯德研究所，巴黎西特大学，巴黎，FranceGaëlleChauveaule Friec，Véronique Meriaux＆Pierre LafayeG5 RNA病毒的进化基因组学，巴黎巴斯德研究所，FranceMatthieu Prot，Deborah Delaune＆EtienneSimonLorièreInstitut de RechercheBiomédicaledesArmées，BrétignysurOrge，FranceDeborah Delaune医学微生物学和感染预防系，阿姆斯特丹UMC，阿姆斯特丹大学分子诊断系，NetherlandsMarion CornelissenAmsterdam阿姆斯特丹感染和免疫研究所，荷兰Smarion Cornelissen，Martin Deijs和Lia van der HoekDepartment of Medical Microbiology and Infection Prevention，Amsterdam UMC，Laboratory of Experimental Virology，University of Amsterdam，Amsterdam，NetherlandsMartin Deijs＆L。

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Julian Buchrieser or Olivier Schwartz.Supplementary informationSupplementary InformationThis file contains Supplementary Information 1-6 and Supplementary Table 1Reporting SummarySupplementary Video 1Time lapse microscopy of TMPRSS2-scarlet-I (red) and HKU1A S-NeonGreen (green) expressing cells.

Julian Buchrieser或Olivier Schwartz。补充信息补充信息本文件包含补充信息1-6和补充表1报告摘要补充视频1 TMPRSS2-scarlet-I（红色）和HKU1A S-NeonGreen（绿色）表达细胞的延时显微镜检查。

293T cells were transfected either with TMPRSS2-scarlet-I or HKU1A S-NeonGreen. At 24 h post transfection the cells were mixed and imaged every 150 seconds for 2.5 h at 37 °C 5% CO2. Two representative movies are shown.Supplementary Video 2Time lapse microscopy of TMPRSS2-scarlet-I (red) and HKU1A S-NeonGreen (green) expressing cells.

用TMPRSS2-scarlet-I或HKU1A S-NeonGreen转染293T细胞。在转染后24小时，将细胞混合并在37℃每150秒成像2.5小时 °C 5%CO2。展示了两部有代表性的电影。补充视频2 TMPRSS2-scarlet-I（红色）和HKU1A S-NeonGreen（绿色）表达细胞的延时显微镜检查。

293T cells were transfected either with TMPRSS2-scarlet-I or HKU1A S-NeonGreen. At 24 h post transfection the cells were mixed and imaged every 150 seconds for 2.5 h at 37 °C 5% CO2. Two representative movies are shown.Rights and permissionsReprints and PermissionsAbout this articleCite this articleSaunders, N., Fernandez, I., Planchais, C.

用TMPRSS2-scarlet-I或HKU1A S-NeonGreen转染293T细胞。在转染后24小时，将细胞混合并在37℃每150秒成像2.5小时 °C 5%CO2。展示了两部有代表性的电影。权利和许可本文的印刷和许可引用本文Saunders，N.，Fernandez，I.，Planchais，C。

et al. TMPRSS2 is a functional receptor for human coronavirus HKU1..

TMPRSS2是人冠状病毒HKU1的功能性受体。。

Nature (2023). https://doi.org/10.1038/s41586-023-06761-7Download citationReceived: 07 April 2023Accepted: 18 October 2023Published: 25 October 2023DOI: https://doi.org/10.1038/s41586-023-06761-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

自然（2023）。https://doi.org/10.1038/s41586-023-06761-7Download引文收稿日期：2023年4月7日接受日期：2023年10月18日发布日期：2023年10月25日OI：https://doi.org/10.1038/s41586-023-06761-7Share本文任何您共享以下链接的人都可以阅读此内容：获取可共享链接抱歉，本文目前不提供可共享链接。复制到文件夹。

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SARS-CoV-2Viral membrane fusionVirus–host interactions

SARS-CoV-2病毒膜融合病毒-宿主相互作用

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