D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage

ABSTRACT Since the D614G substitution in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, the variant strain has undergone a rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage for viral spr...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ya-Wen Cheng, Tai-Ling Chao, Chiao-Ling Li, Sheng-Han Wang, Han-Chieh Kao, Ya-Min Tsai, Hurng-Yi Wang, Chi-Ling Hsieh, You-Yu Lin, Pei-Jer Chen, Sui-Yuan Chang, Shiou-Hwei Yeh
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	furin SARS-CoV-2 spike syncytium Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9809a8e9343e41a8ad2817edd2a2befd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9809a8e9343e41a8ad2817edd2a2befd
record_format	dspace
spelling	oai:doaj.org-article:9809a8e9343e41a8ad2817edd2a2befd2021-11-10T18:37:50ZD614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage10.1128/mBio.00587-212150-7511https://doaj.org/article/9809a8e9343e41a8ad2817edd2a2befd2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00587-21https://doaj.org/toc/2150-7511ABSTRACT Since the D614G substitution in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, the variant strain has undergone a rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage for viral spreading. To explore the mechanism, we analyzed 18 viral isolates containing S proteins with either G614 or D614 (S-G614 and S-D614, respectively). The plaque assay showed a significantly higher virus titer in S-G614 than in S-D614 isolates. We further found increased cleavage of the S protein at the furin substrate site, a key event that promotes syncytium formation, in S-G614 isolates. The enhancement of the D614G substitution in the cleavage of the S protein and in syncytium formation has been validated in cells expressing S protein. The effect on the syncytium was abolished by furin inhibitor treatment and mutation of the furin cleavage site, suggesting its dependence on cleavage by furin. Our study pointed to the impact of the D614G substitution on syncytium formation through enhanced furin-mediated S cleavage, which might increase the transmissibility and infectivity of SARS-CoV-2 strains containing S-G614. IMPORTANCE Analysis of viral genomes and monitoring of the evolutionary trajectory of SARS-CoV-2 over time has identified the D614G substitution in spike (S) as the most prevalent expanding variant worldwide, which might confer a selective advantage in transmission. Several studies showed that the D614G variant replicates and transmits more efficiently than the wild-type virus, but the mechanism is unclear. By comparing 18 virus isolates containing S with either D614 or G614, we found significantly higher virus titers in association with higher furin protease-mediated cleavage of S, an event that promotes syncytium formation and virus infectivity, in the S-G614 viruses. The effect of the D614G substitution on furin-mediated S cleavage and the resulting enhancement of the syncytium phenotype has been validated in S-expressing cells. This study suggests a possible effect of the D614G substitution on S of SARS-CoV-2; the antiviral effect through targeting furin protease is worthy of being investigated in proper animal models.Ya-Wen ChengTai-Ling ChaoChiao-Ling LiSheng-Han WangHan-Chieh KaoYa-Min TsaiHurng-Yi WangChi-Ling HsiehYou-Yu LinPei-Jer ChenSui-Yuan ChangShiou-Hwei YehAmerican Society for MicrobiologyarticlefurinSARS-CoV-2spikesyncytiumMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	furin SARS-CoV-2 spike syncytium Microbiology QR1-502
spellingShingle	furin SARS-CoV-2 spike syncytium Microbiology QR1-502 Ya-Wen Cheng Tai-Ling Chao Chiao-Ling Li Sheng-Han Wang Han-Chieh Kao Ya-Min Tsai Hurng-Yi Wang Chi-Ling Hsieh You-Yu Lin Pei-Jer Chen Sui-Yuan Chang Shiou-Hwei Yeh D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
description	ABSTRACT Since the D614G substitution in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, the variant strain has undergone a rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage for viral spreading. To explore the mechanism, we analyzed 18 viral isolates containing S proteins with either G614 or D614 (S-G614 and S-D614, respectively). The plaque assay showed a significantly higher virus titer in S-G614 than in S-D614 isolates. We further found increased cleavage of the S protein at the furin substrate site, a key event that promotes syncytium formation, in S-G614 isolates. The enhancement of the D614G substitution in the cleavage of the S protein and in syncytium formation has been validated in cells expressing S protein. The effect on the syncytium was abolished by furin inhibitor treatment and mutation of the furin cleavage site, suggesting its dependence on cleavage by furin. Our study pointed to the impact of the D614G substitution on syncytium formation through enhanced furin-mediated S cleavage, which might increase the transmissibility and infectivity of SARS-CoV-2 strains containing S-G614. IMPORTANCE Analysis of viral genomes and monitoring of the evolutionary trajectory of SARS-CoV-2 over time has identified the D614G substitution in spike (S) as the most prevalent expanding variant worldwide, which might confer a selective advantage in transmission. Several studies showed that the D614G variant replicates and transmits more efficiently than the wild-type virus, but the mechanism is unclear. By comparing 18 virus isolates containing S with either D614 or G614, we found significantly higher virus titers in association with higher furin protease-mediated cleavage of S, an event that promotes syncytium formation and virus infectivity, in the S-G614 viruses. The effect of the D614G substitution on furin-mediated S cleavage and the resulting enhancement of the syncytium phenotype has been validated in S-expressing cells. This study suggests a possible effect of the D614G substitution on S of SARS-CoV-2; the antiviral effect through targeting furin protease is worthy of being investigated in proper animal models.
format	article
author	Ya-Wen Cheng Tai-Ling Chao Chiao-Ling Li Sheng-Han Wang Han-Chieh Kao Ya-Min Tsai Hurng-Yi Wang Chi-Ling Hsieh You-Yu Lin Pei-Jer Chen Sui-Yuan Chang Shiou-Hwei Yeh
author_facet	Ya-Wen Cheng Tai-Ling Chao Chiao-Ling Li Sheng-Han Wang Han-Chieh Kao Ya-Min Tsai Hurng-Yi Wang Chi-Ling Hsieh You-Yu Lin Pei-Jer Chen Sui-Yuan Chang Shiou-Hwei Yeh
author_sort	Ya-Wen Cheng
title	D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
title_short	D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
title_full	D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
title_fullStr	D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
title_full_unstemmed	D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage
title_sort	d614g substitution of sars-cov-2 spike protein increases syncytium formation and virus titer via enhanced furin-mediated spike cleavage
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/9809a8e9343e41a8ad2817edd2a2befd
work_keys_str_mv	AT yawencheng d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT tailingchao d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT chiaolingli d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT shenghanwang d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT hanchiehkao d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT yamintsai d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT hurngyiwang d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT chilinghsieh d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT youyulin d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT peijerchen d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT suiyuanchang d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage AT shiouhweiyeh d614gsubstitutionofsarscov2spikeproteinincreasessyncytiumformationandvirustiterviaenhancedfurinmediatedspikecleavage
_version_	1718439891699761152

D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Virus Titer via Enhanced Furin-Mediated Spike Cleavage

Ejemplares similares