|SOROURI, MAHSA - University Of Texas Southwestern Medical Center|
|CHANG, TYRON - University Of Texas Southwestern Medical Center|
|PINKHAM, CHELSEA - University Of Texas Southwestern Medical Center|
|ELDE, NELS - University Of Utah|
|HANCKS, DUSTIN - University Of Texas Southwestern Medical Center|
Submitted to: PLoS Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/9/2020
Publication Date: 12/28/2020
Citation: Sorouri, M., Chang, T., Jesudhasan, P., Pinkham, C.L., Elde, N., Hancks, D.C. 2020. MISTR: A conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict. PLoS Biology. https://www.doi.org/10.1371/journal.pbio.3001045.
Interpretive Summary: Viral pathogen proteins often directly bind host factors during infection to antagonize cellular functions. Hence the question was: could viruses steal genomic information from the host and use them against the host during the course of infection? To understand that bioinformatic analysis were performed to compare human proteome with viral genome and found that one of the pox viruses have a copy of human mitochondrial gene (vMISTRAV). In vitro experiments have confirmed that indeed MISTR proteins are associated with the electron transport chain factors and regulated by distinct stress signals such as interferon-gamma and hypoxia.
Technical Abstract: Pathogen-mediated antagonism leaves distinct “molecular scars” on host genes. Using these scars as a guide, we have uncovered a Mitochondrial STress-Response circuit (MISTR) encoded by vertebrates. MISTR proteins are associated with the electron transport chain factors and regulated by distinct stress signals such as interferon-gamma and hypoxia. Upon stress, specific ultraconserved miRNAs – one of which is embedded in MISTRAV - downregulate MISTR1 followed by replacement by its paralogs MISTR AntiViral (MISTRAV) or MISTR Hypoxia (MISTRH). While cells lacking MISTR1 are more sensitive to apoptotic triggers, cells lacking MISTRAV or expressing the poxvirus-encoded vMISTRAV display resistance to the same insults. Rapid evolution signatures across primate genomes for MISTR1 and MISTRAV indicate repeated antagonism by pathogens. MISTR proteins are ubiquitous as evidenced by homologs in plants, yeasts, and an algal giant virus. MISTR demonstrates the use of evolution-guided studies in the discovery of cellular circuitry interfacing with fundamental biological processes.