TFAP2C and HNRNPK control mTOR cell metabolism and prion propagation

Heterogeneous Nuclear Ribonucleoprotein K ( HNRNPK ) is a limiting factor for prion propagation. However, little is known about its function except that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify epistatic interactors of HNRNPK . We found that deletion of Transcription Factor AP-2γ ( TFAP2C ) mitigated the survival of hnRNP_K-depleted LN-229 and U-251 MG cells, whereas its overexpression hypersensitized cells to the loss of hnRNP_K. HNRNPK ablation induced downregulation of genes related to lipid and glucose metabolism, decreased cellular ATP, and enhanced catabolism through inhibition of the mTOR pathway and activation of AMPK. Conversely, TFAP2C deletion countered the energy crisis resulting from HNRNPK ablation, while its overexpression promoted mTOR anabolic activity. TFAP2C overexpression reduced prion propagation in wild-type cells and neutralized the enhanced prion replication of HNRNPK -suppressed cells. Importantly, mTOR inhibition mimicked the effects of HNRNPK silencing, increasing prion propagation. We conclude that TFAP2C and HNRNPK are genetic interactors controlling cell metabolism and bioenergy and influencing prion propagation potentially through modulation of the mTOR pathway.