title: Deregulation of translation due to post-transcriptional modification of rRNA explains why erm genes are inducible.
abstract: A key mechanism of bacterial resistance to macrolide antibiotics is the dimethylation of a nucleotide in the large ribosomal subunit by erythromycin resistance methyltransferases. The majority of erm genes are expressed only when the antibiotic is present and the erythromycin resistance methyltransferase activity is critical for the survival of bacteria. Although these genes were among the first discovered inducible resistance genes, the molecular basis for their inducibility has remained unknown. Here we show that erythromycin resistance methyltransferase expression reduces cell fitness. Modification of the nucleotide in the ribosomal tunnel skews the cellular proteome by deregulating the expression of a set of proteins. We further demonstrate that aberrant translation of specific proteins results from abnormal interactions of the nascent peptide with the erythromycin resistance methyltransferase-modified ribosomal tunnel. Our findings provide a plausible explanation why erm genes have evolved to be inducible and underscore the importance of nascent peptide recognition by the ribosome for generating a balanced cellular proteome.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA.
authors.forename: Pulkit
authors.initials: P
authors.lastname: Gupta
authors.forename: Shanmugapriya
authors.initials: S
authors.lastname: Sothiselvam
authors.forename: Nora
authors.initials: N
authors.lastname: Vázquez-Laslop
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mankin
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial / Q000235:genetics*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012335:RNA, Ribosomal / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D013211:Staphylococcus aureus / Q000201:enzymology / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D010455:Peptides; D012335:RNA, Ribosomal; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase