"Unlocking the Power of Primal Fear: How it Shields Against Infection"
In a groundbreaking discovery, scientists have identified a new ancestral antiviral pathway, called FEAR (FACT-ETS-1 antiviral response), that provides an interferon-independent antiviral response in mammals. This pathway, which has been counteracted by a conserved poxvirus protein, represents a critical antiviral pathway that must be successfully targeted by several viruses.
The study, published in Nature Microbiology, reveals that the poxvirus protein A51 can block antiviral responses against RNA viruses in moth cells. This finding suggests the existence of a broad-acting antiviral response conserved across vertebrates and invertebrates. The researchers further discovered that A51 specifically interacts with mono-SUMOylated Spt16 (Spt16SUMO), a modification that remains poorly understood in terms of its functional impact on FACT activity.
The FACT complex, which is conserved across eukaryotes, plays important roles in fundamental processes ranging from DNA replication and repair to transcription. However, the study found that A51 tethers Spt16SUMO to microtubules and prevents it from translocating to the nucleus where it engages sites of active transcription and induces expression of the transcription factor ETS-1. Genetic depletion of either FACT components or ETS-1 rescued the replication defects of poxvirus lacking the A51R gene in mammalian cells.
Interestingly, the antiviral activity of FACT was not reliant on intact IFN responses in the host cell. Moreover, the authors found that A51 proteins from diverse poxviruses retain the ability to antagonize Spt16SUMO, highlighting the evolutionary importance of disarming the FEAR pathway.
The discovery of the FEAR pathway has opened up several research avenues. For example, what activates FACT, and how are FACT and Spt16 SUMOylation regulated in response to infection? The authors show that early poxvirus gene expression is required for FACT activation, but the precise nature of the viral ligand(s) or PAMP(s) involved remains to be uncovered. Moreover, whether there are potential upstream components of this pathway is unclear. Further studies will undoubtedly start to unravel the secrets behind this ancestral response pathway that continues to protect us against infection to this day.
Source: <https://www.nature.com/articles/s41564-024-01649-2>
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