Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 26, Pages 14948-14957Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003266117
Keywords
aminoacyl-tRNA; ergosterol; fungi; DUF2156; lipid aminoacylation
Categories
Funding
- Fondation pour la Recherche Medicale (FRM) [DBF20160635713]
- MitoCross'' Laboratory of Excellence [ANR-10-IDEX-0002-02]
- University of Strasbourg
- IDEX from the University of Strasbourg [W17RAT81]
- National Center for Scientific Research
- Meiji University
- French Ministere de l'Enseignement Superieur et de la Recherche
- FRM [DBF20160635713]
- NIH [1R21AI144481-01]
Ask authors/readers for more resources
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-3 beta-O-L-aspartate (Erg-Asp), a conjugated sterol that is produced by the tRNA-dependent addition of aspartate to the 3 beta-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-3 beta-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-tRNA(Asp) (Asp-tRNA(Asp))-and of a Domain of Unknown Function 2156, which actually transfers aspartate from Asp-tRNA(Asp) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available