RNA G-quadruplexes inhibit translation of the PE/PPE transcripts in Mycobacterium tuberculosis.
J Biol Chem
; 300(1): 105567, 2024 Jan.
Article
in En
| MEDLINE
| ID: mdl-38103641
ABSTRACT
The role of RNA G-quadruplexes (rG4s) in bacteria remains poorly understood. High G-quadruplex densities have been linked to organismal stress. Here we investigate rG4s in mycobacteria, which survive highly stressful conditions within the host. We show that rG4-enrichment is a unique feature exclusive to slow-growing pathogenic mycobacteria, and Mycobacterium tuberculosis (Mtb) transcripts contain an abundance of folded rG4s. Notably, the PE/PPE family of genes, unique to slow-growing pathogenic mycobacteria, contain over 50% of rG4s within Mtb transcripts. We found that RNA oligonucleotides of putative rG4s in PE/PPE genes form G-quadruplex structures in vitro, which are stabilized by the G-quadruplex ligand BRACO19. Furthermore, BRACO19 inhibits the transcription of PE/PPE genes and selectively suppresses the growth of Mtb but not Mycobacterium smegmatis or other rapidly growing bacteria. Importantly, the stabilization of rG4s inhibits the translation of Mtb PE/PPE genes (PPE56, PPE67, PPE68, PE_PGRS39, and PE_PGRS41) ectopically expressed in M. smegmatis or Escherichia coli. In addition, the rG4-mediated reduction in PE/PPE protein levels attenuates proinflammatory response upon infection of THP-1 cells. Our findings shed new light on the regulation of PE/PPE genes and highlight a pivotal role for rG4s in Mtb transcripts as regulators of post-transcriptional translational control. The rG4s in mycobacterial transcripts may represent potential drug targets for newer therapies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bacterial Proteins
/
Protein Biosynthesis
/
RNA, Bacterial
/
RNA, Messenger
/
Gene Expression Regulation, Bacterial
/
G-Quadruplexes
/
Mycobacterium tuberculosis
Limits:
Humans
Language:
En
Journal:
J Biol Chem
/
J. biol. chem
/
Journal of biological chemistry
Year:
2024
Document type:
Article
Affiliation country:
India
Country of publication:
Estados Unidos