Scientists at Ohio State University provide evidence that members of a class of proteins called serine incorporator proteins, best known for curbing HIV infection also promote other antiviral activities that increase the production of type I interferons and proinflammatory cytokines. By promoting these signaling pathways of innate immunity, the SERINC restriction factors SERINC3 and SERINC5, protect cells from infection by HIV-1, vesicular stomatitis virus (VSV), and Zika virus.

The authors show SERINC5, usually present in the cell membrane, moves to the outer mitochondrial membrane protein where it forms a protein complex with an adapter protein, MAVS (mitochondrial antiviral signaling), and TRAF6, an E3 ubiquitin ligase—an enzyme that degrades proteins.

Reducing the expression of SERINC5 in target cells, the authors note, increases cellular infection by HIV-1, VSV and an endemic Asian strain of Zika virus. This demonstrates SERINC5 mediates direct antiviral activities in host cells in addition to the indirect inhibition of HIV-1 reported in earlier studies. Probing further into the mechanism, the authors show SERINC5’s antiviral activity depends on its ability to stimulate the expression of type I interferons and NF-kB inflammatory signaling.

These findings are reported in the Science Signaling article, “SERINC proteins potentiate antiviral type I IFN production and proinflammatory signaling pathways.”

Senior author of the paper Shan-Lu Liu, PhD, professor of virology in the Department of Veterinary Biosciences at The Ohio State University says, “Viruses can get around direct antiviral effects, but if this protein can also modulate key pathways without acting directly on the virus, then a virus may have limited capacity to counteract it.”

Restriction factors—proteins produced by host cells to restrict viral infection—interfere either with the entry of virus particles into healthy cells or viral replication mechanisms in the host cell. Earlier studies have shown the restriction factor SERINC5, found in the host cell membrane incorporates into HIV-1 virus particles, blocking their entry into the host cell.

The current study notes SERINC5 also inhibits viral infections by promoting intracellular innate signaling pathways that involves its binding to the adaptor protein MAVS at the mitochondrial membrane. This binding results in MAVS oligomerization and activation of downstream transcriptional regulators that promote the expression of genes that encode antiviral type I IFNs and proinflammatory cytokines like NF-kB.

Shan-Lu Liu, PhD, professor of virology in the Department of Veterinary Biosciences at The Ohio State University is senior author of the paper.

“The aggregation of these proteins means they need each other,” says Liu. “A big complex like this can recruit additional molecules, enhancing the efficiency of the signal transduction pathway.”

The researchers are currently testing whether this function is also effective against SARS-CoV-2, the virus that causes COVID-19.

“If this family of molecules can do this in animals and humans, then you may think about whether it could be used in a broad antiviral therapy,” says Liu. He is optimistic that the efficacy of SERINC proteins in inhibiting viral infection will extend to suppressing the COVID-19 virus.