Evolutionary signatures of host-virus conflict reveal a family of micropeptides regulating mito-immune functions

Abstract

Abstract Genomics has led to an expansive set of predicted genes; yet, functional annotation is rate-limiting. To drive discovery of immune functions, we exploit genomic scars of pathogen-conflict like rapid evolution and virologs. Virologs are host-coding sequences stolen and repurposed by viruses to rewire cells. Classic examples include master regulators SRC, IL-10, and IL-17. To identify novel immune activities, we screened all viral genomes in the database for factors displaying sequence similarity to cellular factors. Subsequent filtering using motif analysis and expression paired with our functional analysis of our top hit - a micropeptide named C15ORF48 - revealed a vertebrate specific MItochondrial STress Response (MISTR) circuit. MISTR consists of related micropeptides that interface with the electron transport chain (ETC). MISTR factors – MISTR1, MISTR Antiviral(AV)/C15ORF48, and MISTR (H)ypoxia are regulated by ultraconserved miRNAs and stress signals such as cytokines, infection, and hypoxia. MISTR factors are encoded by diverse viruses that infect a range of hosts from squirrels to algae; they are shown to be ancient as they are encoded by yeast but ill-defined in any system. We find that cellular MISTR factors shape chemical- and virus-triggered apoptosis, which is counteracted by a viral-MISTR. Emerging data link MISTR functions to inflammatory signaling via modulation of ETC Complex IV. We show that viral-MISTRs antagonize higher-order configurations of the ETC termed supercomplexes – whose precise function has remained of debate. Using viral systems to seed discovery, we identified new dimensions for textbook functions which implicate supercomplexes as an unappreciated battleground in immune defense.