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.

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

“…Our study relies on deliberate expression of ISG15, which has likely widened the window to observe this immune stimulatory function of ISG15 and its underlying mechanisms. By binding to USP18 and stabilizing it, intracellular free ISG15 promotes negative feedback on the type I IFN response in human, but not in mouse (7,26). The question is whether this process would limit the application of free ISG15 as immune adjuvant in human.…”

“…In this way, USP18 and ISG15 mediate negative feedback on IFNAR signaling, which explains the inflammatory phenotype in the ISG15-deficient patients (20). Remarkably, this stabilizing effect of free ISG15 on USP18 is found in humans, but not in mice (26), in which the affinity of the interaction is lower, likely because of the significant divergence in amino acid sequence of ISG15 between species (7).…”

“…ISG15 is also induced by bacterial infections (5,6). Isg15-deficient mice and humans display phenotypes that indicate a role for ISG15 in the protection against infection, but the underlying mechanisms have not been fully elucidated (3,7,8). ISG15 can be conjugated to proteins but also exists in a free form and thus may act by different mechanisms either within or outside the cell.…”

“…Various signal transduction proteins can be ISGylated, and this can affect signaling outcome, as shown in some specific cases (3). Several viruses have developed distinct strategies to counteract ISGylation (7), further indicating that ISGylation plays an important role in the arms race against viral infection.…”

Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity

“…In addition, USP18 is the only known protease that specifically deconjugates interferonstimulated gene product 15 (ISG15), a ubiquitin-like protein, from target proteins [61]. ISG15 is conjugated to lysine residues of substrates in a process called ISGylation, which is catalyzed sequentially by an E1 activating enzyme (Ube1L), an E2 conjugating enzyme (UbcH8), and an E3 ligase (TRIM25 or Herc5) [62]. A broad range of cellular activities, especially type I IFN responses against viruses, are regulated by ISGylation.…”