New Roles for Mitochondria in Shaping Antiviral and Stress Responses

Mitochondria are dynamic organelles vital for energy production with now appreciated roles in immune defense. During microbial infection, mitochondria serve as signaling hubs to induce immune responses to counteract invading pathogens like viruses. Mitochondrial functions are central to a variety of antiviral responses including apoptosis and type I interferon signaling (IFN-I). While apoptosis and IFN-I mediated by Mitochondrial AntiViral Signaling (MAVS) are well-established defenses, new dimensions of mitochondrial biology are emerging as battlefronts during viral infection. Increasingly, it has become apparent that mitochondria serve as reservoirs for distinct cues that trigger immune responses and that alterations in mitochondrial morphology may also tip infection outcomes. To gain insights into the roles of mitochondrial activities in immune function, we developed a novel cell culture model. Using this model, we uncover that a subset of key antiviral genes, known as interferon-stimulated genes (ISG)s, are differentially regulated at the protein level by metabolites in type I and type II IFN-primed human cells. Interestingly, galactose, which enhances mitochondrial activity, triggers selective protein degradation of the ISG IRF1. Notably, glucose-rich conditions, relative to galactose, amplify IFN-γ efficacy to restrict herpes- and poxvirus infection. In contrast, cells in galactose media display no differences in herpes- and poxvirus replication between untreated and IFN-primed conditions. However, overall herpes- and poxvirus replication is decreased in untreated cells grown in galactose media relative to untreated glucose-rich media. Deletion and rescue experiments demonstrate that IRF1 is an essential vaccinia virus restriction factor in glucose/IFN-γ conditions. Furthermore, I find that glucose media enhancement of IFN-γ induced IRF1 protein levels is conserved for nearly one hundred million years of evolution. These data reveal an unappreciated ISG subprogram that, in principle, could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation. In a second project, I carried out studies examining the processing of an exonic miRNA - miR-147 - which is encoded by an ISG protein that localizes to mitochondria. Both the miRNA and host genes have roles in cellular adaptation to stress including antiviral defense. My studies serve as a model to characterize dual-coding transcripts which are an understudied class of genes associated with a variety of cell processes. Using insights from miR-147 I have bioinformatically defined the landscape of dual-coding transcripts encoding a miRNA paired with a protein. Collectively, my studies highlight new layers of cellular regulation that tip infection outcomes and stress responses.

Author dc:creator

• Chang, Tyron

Contributors dc:contributor

• Tagliabracci, Vincent S.
• Conrad, Nicholas
• DeBerardinis, Ralph J.
• Orchard, Robert C.
• Hancks, Dustin C.

• Antiviral Agents
• Interferon Regulatory Factor-1
• Interferon-gamma
• MicroRNAs
• Mitochondria
• Mitochondrial Proteins

Language dc:language

en

Identifier

1596185259

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10817