Researchers have identified two host enzymes that control the replication of picornaviruses by altering the oxidation state of viral RNA polymerase, according to a peer-reviewed study published in Nature Communications.
The scientists conducted porcine genome-wide CRISPR/Cas9 screening to identify methionine sulfoxide reductase B3, known as MSRB3, as an essential factor for foot-and-mouth disease virus (FMDV). Removing MSRB3 inhibited viral replication. Mechanistically, MSRB3 eliminates methionine oxidation on the FMDV 3D polymerase, which stabilizes the viral enzyme's expression.
A second enzyme, radical SAM domain-containing protein 1 (RSAD1), acts in reverse. The researchers found that RSAD1 catalyzes the oxidation of methionine on the 3D polymerase. This modification triggers the polymerase to aggregate, leading to its degradation through the cellular autophagy-lysosome pathway.
This RSAD1-MSRB3 redox cycling mechanism also regulates the stability of 3D polymerases in enterovirus 71 (EV71) and encephalomyocarditis virus (EMCV). The researchers demonstrated that the pathway modulates viral infectivity and disease development both in vitro and in vivo across these picornaviruses, which cause fever, herpes, and myocarditis in humans and animals.
The study was led by researchers at the Lanzhou Veterinary Research Institute of the Chinese Academy of Agricultural Sciences, Lanzhou University, and the Wuhan Institute of Virology. Funding was provided by the National Natural Science Foundation of China, the Chinese Academy of Agricultural Sciences, and the Project of National Center of Technology Innovation for Pigs, among other government programs.
