RNA-dependent sterol aspartylation in fungi

Nathaniel Yakobov, Frédéric Fischer, Nassira Mahmoudi, Yusuke Saga, Christopher D. Grube, Hervé Roy, Bruno Senger, Guillaume Grob, Shunsuke Tatematsu, Daisuke Yokokawa, Isabelle Mouyna, Jean Paul Latgé, Harushi Nakajima, Tetsuo Kushiro, Hubert D. Becker

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Diverting aminoacyl-transfer RNAs (tRNAs) from protein synthesis is a well-known process used by a wide range of bacteria to aminoacylate membrane constituents. By tRNA-dependently adding amino acids to glycerolipids, bacteria change their cell surface properties, which intensifies antimicrobial drug resistance, pathogenicity, and virulence. No equivalent aminoacylated lipids have been uncovered in any eukaryotic species thus far, suggesting that tRNA-dependent lipid remodeling is a process restricted to prokaryotes. We report here the discovery of ergosteryl-3β-O-L-aspartate (Erg-Asp), a conjugated sterol that is produced by the tRNA-dependent addition of aspartate to the 3β-OH group of ergosterol, the major sterol found in fungal membranes. In fact, Erg-Asp exists in the majority of “higher” fungi, including species of biotechnological interest, and, more importantly, in human pathogens like Aspergillus fumigatus. We show that a bifunctional enzyme, ergosteryl-3β-O-L-aspartate synthase (ErdS), is responsible for Erg-Asp synthesis. ErdS corresponds to a unique fusion of an aspartyl-tRNA synthetase—that produces aspartyl-tRNAAsp (Asp-tRNAAsp)—and of a Domain of Unknown Function 2156, which actually transfers aspartate from Asp-tRNAAsp onto ergosterol. We also uncovered that removal of the Asp modifier from Erg-Asp is catalyzed by a second enzyme, ErdH, that is a genuine Erg-Asp hydrolase participating in the turnover of the conjugated sterol in vivo. Phylogenomics highlights that the entire Erg-Asp synthesis/degradation pathway is conserved across “higher” fungi. Given the central roles of sterols and conjugated sterols in fungi, we propose that this tRNA-dependent ergosterol modification and homeostasis system might have broader implications in membrane remodeling, trafficking, antimicrobial resistance, or pathogenicity.

Original languageEnglish
Pages (from-to)14948-14957
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number26
DOIs
Publication statusPublished - 30 Jun 2020

Keywords

  • Aminoacyl-tRNA
  • DUF2156
  • Ergosterol
  • Fungi
  • Lipid aminoacylation

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