ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis

Abstract

Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the scientific community, as we are still far from understanding the molecular mechanisms that operate after virus infection. Interferon-stimulated gene 15 (ISG15) plays an important antiviral role during viral infection. ISG15 catalyzes a ubiquitin-like post-translational modification termed ISGylation, involving the conjugation of ISG15 molecules to de novo synthesized viral or cellular proteins, which regulates their stability and function. Numerous biomedically relevant viruses are targets of ISG15, as well as proteins involved in antiviral immunity. Beyond their role as cellular powerhouses, mitochondria are multifunctional organelles that act as signaling hubs in antiviral responses. In this review, we give an overview of the biological consequences of ISGylation for virus infection and host defense. We also compare several published proteomic studies to identify and classify potential mitochondrial ISGylation targets. Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy.

Interferon-Independent Innate Responses to Cytomegalovirus

“…It is also possible that HCMV manipulates levels of ISG15 to shift monocytes toward the mixed M1/M2 macrophage phenotype that is observed during infection (122) and hypothesized to enhance viral dissemination and persistence (123,124). This is because in the absence of infection, ISG15 plays a role in the maintenance of mitochondrial homeostasis (125). Specifically, ISGylation of mitochondrial components can control mitochondrial function: reducing the rate of oxidative phosphorylation (OXPHOS) and causing a corresponding decrease in mitochondrial reactive oxygen species (ROS) (126).…”

Systems Biology behind immunoprotection of both Sheep and Goats after Sungri/96 PPRV vaccination

“…HERC5 is considered as the major ligating enzyme in ISGylation. This ISGylation of viral proteins was reported to have an inhibitory effect on the viral infection [59], whereas ISGylation of host proteins leads to either activation [59] or increase in stability [60]. HERC6 instead of HERC5 is considered as the major ligating enzyme in mice [61].…”

Cleavage of Desmosomal Cadherins Promotes γ-Catenin Degradation and Benefits Wnt Signaling in Coxsackievirus B3-Induced Destruction of Cardiomyocytes

“…Thus, MDA5 likely plays a role in the immune response to CVB3 infection, inducing IFN gene transcription upon recognition of the CVB3 dsRNA intermediate. Finally, we also determined the expression of another IFN-stimulated gene, ISG15, a small ubiquitin family protein playing an important antiviral role via ubiquitin-like modification of viral or host proteins (Loeb and Haas, 1992;Albert et al, 2018). ISG15 has been shown to defend against heart failure in virus-induced cardiomyopathy (Rahnefeld et al, 2014).…”