The antiviral role of ISG15 and ISGylation during respiratory RNA virus infection

Lindsay Grace Miller

Interferon Stimulated Gene 15 (ISG15) is a ubiquitin-like protein which is typically induced as part of the interferon-mediated innate immune response to viral infection. ISG15 exerts its antiviral function through either: conjugation to target proteins via a covalent modification, or by its release as an extracellular protein. As a post-translational modification, ISGylation can affect the function of proteins through improper folding, impaired ubiquitination, etc. As such, ISGylation of both host and viral proteins can lead to reduced virus replication. Though its specific role during viral infection has been studied, much of the mechanism isn’t fully understood. We found that ISGylation is induced during infection with Human Parainfluenza Virus Type 3 (HPIV3). HPIV3 is a clinically relevant paramyxovirus, which most severely effects immunocompromised individuals, the elderly, and children by causing diseases such as croup, pneumonia, and bronchiolitis. During infection, we found that ISGylation is antiviral by impairing the budding of HPIV3. Specifically, our study revealed that the HPIV3 Matrix (M) protein is ISGylated, and this event affects the release of M VLPs as well as the localization of the M protein. Our research not only revealed insights to the innate immune response to HPIV3 infection, but it also identified a specific mechanism by which ISGylation exerts its antiviral function.ISG15 is also antiviral when released as an unconjugated protein into the extracellular space. It has been shown to interact with immune cells to induce the release of cytokines, such as IFN-γ. We found that ISG15 can also be released during infection with RSV (another clinically important RNA virus which affects sensitive groups) and that released ISG15 can induce ISGylation and intracellular ISG15 expression independent of IFNs. Furthermore, we identified an RGD-like motif on ISG15 which can interact with α5β1 surface integrins to activate focal adhesion kinases (FAKs). Intracellular ISG15 protein is subsequently stabilized and ISGylation is induced in cells in a mechanism apart from mRNA expression and upregulation. IFN- independent ISGylation can then be induced in both infected and uninfected bystander cells, which leads to a reduction in RSV replication. Thus, our studies elucidate the role of ISG15 as an antiviral protein through both conjugation and release and identify a novel mechanism by which ISG15 can induce ISGylation independent of interferons.

The antiviral role of ISG15 and ISGylation during respiratory RNA virus infection

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