Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus

3C protease (3Cpro), a chymotrypsin-like cysteine protease encoded by the foot-and-mouth disease virus (FMDV), plays an essential role in processing the FMDV P1 polyprotein into individual viral capsid proteins in FMDV replication. Previously, it has been shown that 3Cpro is involved in the blockage...

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Autores principales:	Pathum Ekanayaka, Sung Ho Shin, Prasanna Weeratunga, Hyuncheol Lee, Tae-Hwan Kim, Kiramage Chathuranga, Ashan Subasinghe, Jong-Hyeon Park, Jong-Soo Lee
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	FMDV 3Cpro RIG-I MDA5 3Cpro C142T substitution attenuated virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9cb0fd68eb60406d85ed97bf304d6fdb
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spelling	oai:doaj.org-article:9cb0fd68eb60406d85ed97bf304d6fdb2021-11-19T05:30:19ZFoot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus1664-302X10.3389/fmicb.2021.737031https://doaj.org/article/9cb0fd68eb60406d85ed97bf304d6fdb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.737031/fullhttps://doaj.org/toc/1664-302X3C protease (3Cpro), a chymotrypsin-like cysteine protease encoded by the foot-and-mouth disease virus (FMDV), plays an essential role in processing the FMDV P1 polyprotein into individual viral capsid proteins in FMDV replication. Previously, it has been shown that 3Cpro is involved in the blockage of the host type-I interferon (IFN) responses by FMDV. However, the underlying mechanisms are poorly understood. Here, we demonstrated that the protease activity of 3Cpro contributed to the degradation of RIG-I and MDA5, key cytosolic sensors of the type-I IFN signaling cascade in proteasome, lysosome and caspase-independent manner. And also, we examined the degradation ability on RIG-I and MDA5 of wild-type FMDV 3Cpro and FMDV 3Cpro C142T mutant which is known to significantly alter the enzymatic activity of 3Cpro. The results showed that the FMDV 3Cpro C142T mutant dramatically reduce the degradation of RIG-I and MDA5 due to weakened protease activity. Thus, the protease activity of FMDV 3Cpro governs its RIG-I and MDA5 degradation ability and subsequent negative regulation of the type-I IFN signaling. Importantly, FMD viruses harboring 3Cpro C142T mutant showed the moderate attenuation of FMDV in a pig model. In conclusion, our results indicate that a novel mechanism evolved by FMDV 3Cpro to counteract host type-I IFN responses and a rational approach to virus attenuation that could be utilized for future vaccine development.Pathum EkanayakaSung Ho ShinPrasanna WeeratungaHyuncheol LeeHyuncheol LeeTae-Hwan KimTae-Hwan KimKiramage ChathurangaAshan SubasingheJong-Hyeon ParkJong-Soo LeeFrontiers Media S.A.articleFMDV 3CproRIG-IMDA53Cpro C142T substitutionattenuated virusMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FMDV 3Cpro RIG-I MDA5 3Cpro C142T substitution attenuated virus Microbiology QR1-502
spellingShingle	FMDV 3Cpro RIG-I MDA5 3Cpro C142T substitution attenuated virus Microbiology QR1-502 Pathum Ekanayaka Sung Ho Shin Prasanna Weeratunga Hyuncheol Lee Hyuncheol Lee Tae-Hwan Kim Tae-Hwan Kim Kiramage Chathuranga Ashan Subasinghe Jong-Hyeon Park Jong-Soo Lee Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
description	3C protease (3Cpro), a chymotrypsin-like cysteine protease encoded by the foot-and-mouth disease virus (FMDV), plays an essential role in processing the FMDV P1 polyprotein into individual viral capsid proteins in FMDV replication. Previously, it has been shown that 3Cpro is involved in the blockage of the host type-I interferon (IFN) responses by FMDV. However, the underlying mechanisms are poorly understood. Here, we demonstrated that the protease activity of 3Cpro contributed to the degradation of RIG-I and MDA5, key cytosolic sensors of the type-I IFN signaling cascade in proteasome, lysosome and caspase-independent manner. And also, we examined the degradation ability on RIG-I and MDA5 of wild-type FMDV 3Cpro and FMDV 3Cpro C142T mutant which is known to significantly alter the enzymatic activity of 3Cpro. The results showed that the FMDV 3Cpro C142T mutant dramatically reduce the degradation of RIG-I and MDA5 due to weakened protease activity. Thus, the protease activity of FMDV 3Cpro governs its RIG-I and MDA5 degradation ability and subsequent negative regulation of the type-I IFN signaling. Importantly, FMD viruses harboring 3Cpro C142T mutant showed the moderate attenuation of FMDV in a pig model. In conclusion, our results indicate that a novel mechanism evolved by FMDV 3Cpro to counteract host type-I IFN responses and a rational approach to virus attenuation that could be utilized for future vaccine development.
format	article
author	Pathum Ekanayaka Sung Ho Shin Prasanna Weeratunga Hyuncheol Lee Hyuncheol Lee Tae-Hwan Kim Tae-Hwan Kim Kiramage Chathuranga Ashan Subasinghe Jong-Hyeon Park Jong-Soo Lee
author_facet	Pathum Ekanayaka Sung Ho Shin Prasanna Weeratunga Hyuncheol Lee Hyuncheol Lee Tae-Hwan Kim Tae-Hwan Kim Kiramage Chathuranga Ashan Subasinghe Jong-Hyeon Park Jong-Soo Lee
author_sort	Pathum Ekanayaka
title	Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
title_short	Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
title_full	Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
title_fullStr	Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
title_full_unstemmed	Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus
title_sort	foot-and-mouth disease virus 3c protease antagonizes interferon signaling and c142t substitution attenuates the fmd virus
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/9cb0fd68eb60406d85ed97bf304d6fdb
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Foot-and-Mouth Disease Virus 3C Protease Antagonizes Interferon Signaling and C142T Substitution Attenuates the FMD Virus

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