Abstract
The type I interferon system plays a critical role in limiting the spread of viral infection. Viruses induce the production of interferon (IFN), which after binding to the IFN-α/β receptor (IFNAR), and triggering of the JAK/STAT signaling cascade, results in the induction of interferon-stimulated genes (ISGs). These ISGs function to inhibit viral replication and to regulate the host immune response. Among these ISGs, the ubiquitin-like molecule, ISG15, is one of the most strongly induced proteins. Similar to ubiquitin, through an IFN induced conjugation cascade, ISG15 is covalently linked to a variety of cellular proteins, suggesting regulation of different cellular processes. Studies performed over the past several years have shown that ISG15 plays a central role in the host’s antiviral response against many viruses. Mice lacking ISG15 display increased susceptibility to multiple viruses. Furthermore, several viruses have developed immune evasion strategies that directly target the ISG15 pathway. Work is now underway to determine the mechanism by which ISG15 functions as an antiviral molecule, such that therapies targeting this pathway can be developed in the future.
Highlights
The ISG15 overexpression siRNA (ISG15) PathwayISG15 was first noted in type I interferon (IFN; IFN, -β) treated cell lysates in 1984 and was soon after identified as having sequence homology to ubiquitin [2,3]
When an human papillomavirus (HPV) pseudovirus system was utilized to determine if ISGylation impacted infectivity, the authors found that HPV16 pseudovirus generated in cells cotransfected with ISG15, E1, E2, and E3 resulted in decreased infectivity of the virus [24]
Significant progress has been made in identifying the components of the ISG15 conjugation cascade, understanding how these proteins are induced during viral infection, and identifying potential targets for ISGylation
Summary
ISG15 was first noted in type I interferon (IFN; IFN- , -β) treated cell lysates in 1984 and was soon after identified as having sequence homology to ubiquitin (reviewed in reference [1]) [2,3]. ISG15 is one of the most abundantly-induced transcripts upon type I IFN treatment, as well as following TLR ligation and viral infection [3,4] It is synthesized as a 17 kDa precursor protein that is proteolytically processed into its mature 15 kDa form [3]. Following stimulation with type I IFN, ISG15 exists in three distinct states- free within the cell, released into the extracellular space, or conjugated to target proteins. The recent observation that Herc mediates the ISGylation of actively translated proteins would make many of these IFN induced proteins important targets [24] It would provide additional support for ISG15 playing a significant role during viral infection. The importance of ISG15 in the host response to viral infection has been confirmed in (1) studies evaluating the impact of ISG15 overexpression/knockdown on viral growth in vitro; (2) studies of mice deficient in members of the ISG15 conjugation cascade; and (3) the evaluation of viral immune evasion strategies targeting ISG15
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