Prof. Hubert D. Becker
Université de Strasbourg, CNRS, Génétique Moléculaire, Génomique, Microbiologie, France
Filamentous fungi use aminoacyl-tRNAs to reshape sterols.
Rerouting aminoacyl-tRNAs from protein synthesis to aminoacylate cell wall constituents, is a well-known process used by a wide range bacteria. By tRNA-dependently adding amino acids to peptidoglycan or glycerolipids, bacteria change the properties of their cell surface which intensifies their resistance to antimicrobial drugs, their pathogenicity and virulence. This process is carried out by a widespread family of enzymes called MprF in bacteria and archaea. MprFs belong to a broad family of enzymes called aminoacyl-tRNA transferases (AATs) that transfer the amino acid from an aminoacyl-tRNA donor onto an accepting secondary substrate which in the case of MprF is a glycerolipid. No equivalent aminoacylated lipids had been uncovered in any eukaryotic species thus far, suggesting that tRNA-dependent lipid remodelling is a process restricted to prokaryotes.
By combining bioinformatic- biochemical- and genetic approaches we discovered a new sub-family of AAT, the steryl-amino acid synthases which transfer either aspartate or glycine from Asp-tRNAsp or Gly-tRNAGly respectively, onto the 3b-OH group of ergosterol (Erg) thereby generating a new class of conjugated sterols: ergosteryl-3b-O-L-aspartate (Erg-Asp) or ergosteryl-3ß-O-glycine. The two enzymes that generates these two ergosteryl-amino acids are called ergosteryl-3ß-O-aspartate synthase (ErdS) and ergosteryl-3ß-O-glycine synthase (ErgS) and are wide spread among fungi, including species of biotechnological interest (Neurospora crassa, Aspergillus oryzae) and, importantly, human opportunistic pathogens (Aspergillus fumigatus, Cryptococcus neoformans). We also uncovered that removal of the Asp modifier from Erg-Asp is catalysed by a second enzyme, ErdH that is a genuine Erg-Asp hydrolase participating in the turnover of conjugated sterol in vivo.
Sterol modifications influence multiple central biological processes, in particular membrane trafficking, antimicrobial resistance and autophagy as well as pathogenicity in various fungi. We haven’t yet discovered the physiological role or roles these ergosteryl-amino acids play in fungi, but have preliminary results suggesting that they might be involved in escaping the immune system of infected hosts.
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