ISG15: It's Complicated

Abstract

Interferon-stimulated gene product 15 (ISG15) is a key component of host responses to microbial infection. Despite having been known for four decades, grasping the functions and features of ISG15 has been a slow and elusive process. Substantial work over the past two decades has greatly enhanced this understanding, revealing the complex and variable nature of this protein. This has unveiled multiple mechanisms of action that are only now beginning to be understood. In addition, it has uncovered diversity not only between how ISG15 affects different pathogens but also between the function and structure of ISG15 itself between different host species. Here we review the complexity of ISG15 within the context of viral infection, focusing primarily on its antiviral function and the mechanisms viruses employ to thwart its effects. We highlight what is known regarding the impact of ISG15 sequence and structural diversity on these interactions and discuss the aspects presenting the next frontier toward elucidating a more complete picture of ISG15 function.

Graphical abstract

Highlights

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  ISG15 is one of the most highly upregulated IFN-stimulated proteins.

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  ISG15 is involved in numerous pathways with multiple mechanisms of action.

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  Viruses encode specific countermeasures to combat ISG15 function.

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  ISG15 possesses interspecies sequence diversity impacting structure, function, and viral interactions.

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  Key advances have been made; much work remains to grasp the complexity of ISG15.