Regulation of gene expression by macrolide-induced ribosomal frameshifting.
The expression of many genes is controlled by upstream ORFs (uORFs). Typically, the progression of the ribosome through a regulatory uORF, which depends on the physiological state of the cell, influences the expression of the downstream gene. In the classic mechanism of induction of macrolide resistance genes, antibiotics promote translation arrest within the uORF, and the static ribosome induces a conformational change in mRNA, resulting in the activation of translation of the resistance cistron. We show that ketolide antibiotics, which do not induce ribosome stalling at the uORF of the ermC resistance gene, trigger its expression via a unique mechanism. Ketolides promote frameshifting at the uORF, allowing the translating ribosome to invade the intergenic spacer. The dynamic unfolding of the mRNA structure leads to the activation of resistance. Conceptually similar mechanisms may control other cellular genes. The identified property of ketolides to reduce the fidelity of reading frame maintenance may have medical implications.
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.
Pulkit
P
Gupta
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.
Krishna
K
Kannan
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA. Electronic address: shura@uic.edu.
Alexander S
AS
Mankin
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA. Electronic address: nvazquez@uic.edu.
Nora
N
Vázquez-Laslop
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001483:Base Sequence; D018965:Frameshifting, Ribosomal / Q000187:drug effects* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D048628:Ketolides / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D008780:Methyltransferases / Q000235:genetics; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000187:drug effects; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics*
D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; D012333:RNA, Messenger; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase