Convergent evolution of metabolic regulation governs redox adaptation in Toxoplasma.

Abstract

Diverse organisms adjust metabolic gene expression during crowding as they encounter nutrient scarcity, oxidative stress, and waste accumulation. Apicomplexan parasites experience these stresses during intracellular growth within host cells yet lack known regulators of metabolic adaptation. We screened the apicomplexan parasite Toxoplasma gondii to identify genes that support parasite fitness during crowding. Nicotinamide adenine dinucleotide (NAD)(P)⁺ biosynthesis was required at high parasite density, along with several parasite-specific factors, including an RNA-binding protein we named "T. gondii parasite response to oxidation" (TgPRO). TgPRO loss elevated reactive oxygen species under ambient conditions, which was rescued by growth at low oxygen levels. TgPRO regulates the expression of transcripts involved in carbon metabolism and iron-sulfur cluster assembly. Regulation of the iron-sulfur cluster assembly protein ISCU relies on TgPRO binding to the transcript's 3' UTR. Through convergent evolution, TgPRO performs a role analogous to that of known metabolic regulators from other species, representing the first dedicated regulator of metabolic gene expression in apicomplexans.