RNA virus
Why do coronavirus and alphavirus recognize and remove ADP-ribosylation?
Macrodomain ADP-ribosylhydrolase is critical for viral replication and virulence
Macrodomain is a relatively small protein fold consisting of ~150 amino acids which has been identified in humans and pathogens, including all coronaviruses. Most macrodomains bind to the small molecule ADP-ribose and ADP-ribosylated proteins. Recent data revealed that a subset of macrodomain in humans and viruses possesses enzymatic activity to hydrolyze ADP-ribose from ADP-ribosylated proteins. For example, these enzymatically active macrodomains are present in a subset of positive-stranded RNA viruses, including coronaviruses, alphaviruses, rubella virus, and hepatitis E virus.
The ability to bind and remove ADP-ribose is critical for viral replication and virulence, making macrodomain an attractive antiviral target.
Dasovich M, Zhuo J, Goodman JA, Thomas A, McPherson RL, Jayabalan AK, Busa VF, Cheng SJ, Murphy BA, Redinger KR, Alhammad YMO, Fehr AR, Tsukamoto T, Slusher BS, Bosch J, Wei H, Leung AKL. High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain. ACS Chem Biol. 2021 Dec 14 [Abstract/PDF]
McPherson RL, Abraham R, Sreekumar E, Ong SE, Cheng SJ, Baxter VK, Kistemaker HA, Filippov DV, Griffin DE, Leung AK. ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1666-1671. [Abstract/PDF]
Leung AKL, McPherson RL, Griffin DE. Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases. PLoS Pathog. 2018 Mar 22;14(3):e1006864. [Abstract/PDF]
Virus disrupts stress granules by removing ADP-ribosylation
We discovered that alphaviruses direct the compositional control of cellular condensates during infections through macrodomain to remove ADP-ribosylation. Macrodomain ADP-ribosylhydrolase not only breaks down stress granules but also forms another class of condensates that lack translation factors but contain other stress granule components (e.g., G3BP1). These data suggest that the virus breaks down the protein–ADP-ribose–protein network within stress granules so that the translation factors and viral RNAs are released for selective translation of viral proteins.
Jayabalan AK, Adivarahan S, Koppula A, Abraham R, Batish M, Zenklusen D, Griffin DE, Leung AKL. Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity. Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2021719118. [Abstract/PDF]
Given that Nature selects ADP-ribosylation as a target in dissolving stress granules, our findings may provide a new therapeutic avenue to disassemble stress granule-like aggregates in neurodegenerative diseases. e.g., those induced by ALS mutations.