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

Pathum Ekanayaka; Sung Ho Shin; Prasanna Weeratunga; Hyuncheol Lee; Tae-Hwan Kim; Kiramage Chathuranga; Ashan Subasinghe; Jong-Hyeon Park; Jong-Soo Lee

doi:10.3389/fmicb.2021.737031

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

Front Microbiol. 2021 Nov 19:12:737031. doi: 10.3389/fmicb.2021.737031. eCollection 2021.

Authors

Affiliations

¹ College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea.
² Animal and Plant Quarantine Agency, Gyeongsangbuk-do, South Korea.
³ California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, United States.
⁴ Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.

Abstract

3C protease (3C^pro), 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 3C^pro 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 3C^pro 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 3C^pro and FMDV 3C^pro C142T mutant which is known to significantly alter the enzymatic activity of 3C^pro. The results showed that the FMDV 3C^pro C142T mutant dramatically reduce the degradation of RIG-I and MDA5 due to weakened protease activity. Thus, the protease activity of FMDV 3C^pro governs its RIG-I and MDA5 degradation ability and subsequent negative regulation of the type-I IFN signaling. Importantly, FMD viruses harboring 3C^pro C142T mutant showed the moderate attenuation of FMDV in a pig model. In conclusion, our results indicate that a novel mechanism evolved by FMDV 3C^pro to counteract host type-I IFN responses and a rational approach to virus attenuation that could be utilized for future vaccine development.

Keywords: 3Cpro C142T substitution; FMDV 3Cpro; MDA5; RIG-I; attenuated virus.