Title : A haploid genetic screen identifies the major facilitator
domain containing
2A (MFSD2A ) transporter as a key mediator in the response to tunicamycin
Abstract :
- Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosylation, protein palmitoylation, ganglioside production, proteoglycan synthesis , 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, and cell wall biosynthesis in bacteria
- Treatment of cells with TM elicits endoplasmic reticulum stress and activates the unfolded protein response
- Although widely used in laboratory settings for many years, it is unknown how TM enters cells
- Here, we identify in an unbiased genetic screen a transporter of the major facilitator superfamily, major facilitator domain containing 2A (MFSD2A ), as a critical mediator of TM toxicity
- Cells without MFSD2A are TM-resistant, whereas MFSD2A-overexpressing cells are hypersensitive
- Hypersensitivity is associated with increased cellular TM uptake concomitant with an enhanced endoplasmic reticulum stress response
- Furthermore, MFSD2A mutant analysis reveals an important function of the C terminus for correct intracellular localization and protein stability, and it identifies transmembrane helical amino acid residues essential for mediating TM sensitivity
- Overall, our data uncover a critical role for MFSD2A by acting as a putative TM transporter at the plasma membrane