RNA-dependent sterol aspartylation in fungi

Significance Bacteria are known to add amino acids (aa) to membrane lipids to resist antimicrobials and escape immune responses. This surface lipid aminoacylation process requires diverting aminoacyl-tRNAs from protein synthesis. While widespread in bacteria, no analogous lipid remodeling system had thus far been evidenced in eukaryotes. We uncovered that most fungi tRNA-dependently add aspartate onto ergosterol (ergosteryl-3β- O - l -aspartate [Erg-Asp]), the major sterol found in fungal membranes. Asp addition is catalyzed by an ergosteryl-3β- O - l -aspartate synthase (ErdS) and its removal by a dedicated hydrolase (ErdH). This pathway is conserved across “higher” fungi, including pathogens. Given the central roles of sterols and derivatives in fungi, we propose that the Erg-Asp homeostasis system might impact membrane remodeling, trafficking, antimicrobial resistance, or pathogenicity.