Image courtesy of the
University of North Carolina
Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.
The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.
The team believes this finding could have a range of therapeutic implications.
“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.
Dr Zhu and his colleagues described this research in Cell Host and Microbe.
The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”
To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”
Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.
The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.
Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.
When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.
For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.
