Newswise – COLUMBUS – Scientists have discovered that a family of proteins, best known for their ability to reduce HIV infection, may also have the potential to defeat other emerging and emerging viruses.
The secret to their new power is in enhancing immune cells’ signals to activate type I interferons, one of the most powerful fighters in the innate viral response.
Cell culture experiments showed that these proteins from the SERINC SERINC group helped cells resist infection by Zika, HIV and Ebola viruses. Researchers are now testing whether this function can also be used against SARS-CoV-2 which causes COVID .
It is one thing for a protein that acts directly against a particular virus. This has been demonstrated by SERINC5’s incorporation into the HIV particle during its viral production. It’s quite another to show that a protein enhances an antiviral cell signaling pathway after infection of host cells. Shan-Lu Liu is a senior study author and professor of virology at The Ohio state University.
“Viruses are able to bypass direct antiviral effects,” stated Liu, who is also an investigator at Ohio State’s Center for Retrovirus Research. A virus might be able to counteract it if the protein is able to modulate key pathways, but not directly.
“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.”
The research is published today (Sept. 14, 2021) in the journal Science Signaling.
Liu studied the evolutionary arms race between HIV and the immune system over many years. He led a 2019 research that showed how a Nef HIV protein can win that fight, specifically by interfering in virus-producing cells with SERINC proteins. In this study, Liu and his colleagues examined the functions of SERINC5 in target cells during the next stage of viral infection. They discovered that SERINC5 not only boosts the production of type I interferons but also has the same effect upon the signaling that produces NF-kB inflammatory cytokines.
SERINC5 does not modulate this signaling process by itself, but it works with proteins MAVS and TRAF6. Liu stated that some of the behaviors it exhibits are still unknown.
In cultures containing viral infection, researchers discovered that SERINC5 moves from the cell surface to the membrane surrounding the mitochondria. This is a very unusual behavior. Once it was there, SERINC5 teamed with MAVS, TRAF6 and formed a large, multifaceted complex. This is likely to explain why its role in the signaling pathway is so important.
“The aggregation means that these proteins need each other – and it’s an exciting discovery,” Liu, who is also codirector of the Viruses and Emerging Pathogens Program at Ohio State University’s Infectious Diseases Institute. “A big complex like this can recruit additional molecules, enhancing the efficiency of the signal transduction pathway.”
These recruited molecules are part of a cascade of messages that lead to type I interferon production and NF-kB inflammatory cytokines from virus-infected cells, both of which play a crucial role in limiting viral infection in the early stage. This mechanism was shown to prevent infection by Zika, Ebola, and HIV viruses in multiple cell types.
In contrast, cells that were not modified to produce the SERINC5 proteins in response to HIV, Ebola, and Zika viruses took over the cells and reproduced more. This suggests how crucial SERINC is in the mechanism that activates the primary antiviral response from host cells.
This work was done in two members the SERINC3 family, SERINC5 and SERINC5, although Liu speculated that there may be other versions. There is much to be learned, such as the triggers that cause SERINC5’s relocation from the cell surface into mitochondria and its normal cellular functions when there are no viruses around.
Liu is positive that the protein’s functions will be able to suppress the COVID -19 virus. My speculation is that the SERINC protein will have an effect, because type I interferons play a crucial role in controlling a virus’ early stages. This molecule can increase the type I interferon response. “Finding one protein that can modulate a key pathway that has a broad antiviral effect – well, you can imagine this protein has a broad antiviral function.”
This work was supported by the National Institutes of Health and the National Cancer Institute (NCI).
Coauthors are Cong Zeng and Tianliang Li as well as Jingyou Yu and Yi-Min Zheng. They also collaborated with Jacob Yount and Haitao Youn. All of Ohio State and Abdul Waheed and Eric Freed from the NCI HIV Dynamics and Replication Program.
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