Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals

Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum me-tabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.

Automated summary

A genetic analysis linking serum metabolites to membrane transporters revealed a connection between FLVCR1 and phosphocholine. FLVCR1 loss impairs choline metabolism and leads to mitochondrial defects and upregulation of the integrated stress response. The findings suggest FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.