MISTR : a conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict.

Abstract

As pathogens manipulate host-encoded master regulators, we hypothesized that molecular scars of host-pathogen conflicts-such as signatures of rapid evolution and viral mimics-could lead to the discovery of novel cellular functions. Indeed, our evolution-guided screens have identified MItochondrial STress Response (MISTR), a cellular circuit conserved in vertebrates. MISTR proteins are associated with electron transport chain (ETC) factors and activated by stress signals such as interferon-gamma and hypoxia. Importantly, MISTR homologs are present in yeast, Plasmodium, plants, and diverse viruses. Upon stress, ultraconserved miRNAs downregulate MISTR1 followed by replacement with paralogs MISTRAV and/or MISTRH. While cells lacking MISTR1 are more sensitive to chemical and viral apoptotic triggers, cells lacking MISTRAV or expressing the squirrelpox virus-encoded vMISTRAV exhibit resistance to the same insults. MISTR1, which acts as the central axis of the MISTR circuit, is a constitutively expressed protein associated with Complex IV (CIV) of the ETC. In agreement with a role in oxidative phosphorylation (OXPHOS), MISTR1 KO cells display reduced proliferation and cellular ATP levels compared to WT cells when switched from glucose-containing media; yet this defect is grossly attenuated when the cells are grown in galactose-containing media for several days prior to assay indicating the presence of a compensatory mechanism. A recently published structure of CIV illustrates that MISTR1 lies at the dimeric interface of CIV homodimers, which may prevent CIV dimerization. Given CIV exhibits higher activity in its monomeric form, we hypothesize that the observed defects in cellular proliferation and ATP production in the absence of MISTR1 are due to dimerization of CIV. Furthermore, our data support a model where stress-induced miRNAs downregulate MISTR1 to decrease ETC activity and reduce reactive oxygen species generation. Overall, the findings presented in this dissertation suggest that MISTR1 is a master regulator of OXPHOS and cell death in a stress response circuit regulated by related miRNAs and targeted by viruses. Furthermore, the discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal fundamental biological processes.