TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.
TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.
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DOI：
10.1016/j.cell.2023.06.005
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发表时间：
2023-08-03
期刊：
影响因子：
64.5
通讯作者：
Daelemans, Dirk
中科院分区：
文献类型：
--
作者：
Baggen, Jim;Jacquemyn, Maarten;Persoons, Leentje;Vanstreels, Els;Pye, Valerie E.;Wrobel, Antoni G.;Calvaresi, Valeria;Martin, Stephen R.;Roustan, Chloe;Cronin, Nora B.;Reading, Eamonn;Thibaut, Hendrik Jan;Vercruysse, Thomas;Maes, Piet;Smet, Frederik De;Yee, Angie;Nivitchanyong, Toey;Roell, Marina;Franco-Hernandez, Natalia;Rhinn, Herve;Mamchak, Alusha Andre;Young-Chapon, Maxime Ah;Brown, Eric;Cherepanov, Peter;Daelemans, Dirk
SARS-CoV-2与广泛的组织亲和性有关，这一特征通常由宿主细胞上的进入受体的可用性决定。在这里，我们发现TMEM106B是一种溶酶体跨膜蛋白，可以作为SARS-CoV-2进入血管紧张素转换酶2 （ACE2）阴性细胞的替代受体。刺突替代E484D增加了TMEM106B结合，从而增强了TMEM106B介导的进入。TMEM106B特异性单克隆抗体阻断SARS-CoV-2感染，证明TMEM106B在病毒进入中的作用。利用x射线晶体学、低温电子显微镜（cro - em）和氢-氘交换质谱（HDX-MS），我们发现TMEM106B的腔域（LD）与SARS-CoV-2尖峰的受体结合基序有关。最后，我们发现TMEM106B促进刺突介导的合胞体形成，表明TMEM106B在病毒融合中的作用。总之，我们的研究结果确定了一种不依赖ace2的SARS-CoV-2感染机制，该机制涉及与受体硫酸肝素和TMEM106B的合作相互作用。TMEM106B直接参与SARS-CoV-2刺突替代的受体结合域E484D增加TMEM106B结合，增强TMEM106B介导的进入TMEM106B特异性抗体中和SARS-CoV-2感染TMEM106B促进刺突介导的合胞体形成溶酶体跨膜蛋白TMEM106B可作为SARS-CoV-2进入ace2阴性细胞的替代受体。刺突替代E484D改善刺突与TMEM106B的结合，增强TMEM106B介导的SARS-CoV-2感染。
SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B. TMEM106B directly engages the receptor-binding domain of SARS-CoV-2 spike Substitution E484D increases TMEM106B binding, enhancing TMEM106B-mediated entry TMEM106B-specific antibodies neutralize SARS-CoV-2 infection TMEM106B promotes spike-mediated syncytium formation The lysosomal transmembrane protein TMEM106B can serve as an alternative receptor for SARS-CoV-2 entry into ACE2-negative cells. Spike substitution E484D improves spike binding to TMEM106B, enhancing TMEM106B-mediated SARS-CoV-2 infection.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
影响因子：
3.5
作者：
Brady, Owen A.;Zheng, Yanqiu;Hu, Fenghua
通讯作者：
Hu, Fenghua
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
12.7
作者：
Feng T;Lacrampe A;Hu F
通讯作者：
Hu F