Ribosome Rescue Pathways in Bacteria

Abstract

Ribosomes that become stalled on truncated or damaged mRNAs during protein synthesis must be rescued for the cell to survive. Bacteria have evolved a diverse array of rescue pathways to remove the stalled ribosomes from the aberrant mRNA and return them to the free pool of actively translating ribosomes. In addition, some of these pathways target the damaged mRNA and the incomplete nascent polypeptide chain for degradation. This review highlights the recent developments in our mechanistic understanding of bacterial ribosomal rescue systems, including drop-off, trans-translation mediated by transfer-messenger RNA and small protein B, ribosome rescue by the alternative rescue factors ArfA and ArfB, as well as Bacillus ribosome rescue factor A, an additional rescue system found in some Gram-positive bacteria, such as Bacillus subtilis. Finally, we discuss the recent findings of ribosome-associated quality control in particular bacterial lineages mediated by RqcH and RqcP. The importance of rescue pathways for bacterial survival suggests they may represent novel targets for the development of new antimicrobial agents against multi-drug resistant pathogenic bacteria.

RqcH and RqcP catalyze processive poly-alanine synthesis in a reconstituted ribosome-associated quality control system

“…Damaged or truncated mRNAs are harmful to cells because they sequester ribosomes from active protein production and can result in the synthesis of cytotoxic truncated proteins ( 1 ). Therefore, diverse ribosome rescue pathways have evolved in all domains of life to disassemble stalled ribosomal complexes ( 2–4 ). The first ribosome rescue pathway to be identified in bacteria was the trans-translation system ( 5 ).…”

“…This, in turn, marks the aberrant proteins for degradation by ClpA, ClpXP and FtsH proteases ( 9 ). In addition to the trans-translation system, Escherichia coli possess two alternative rescue systems that are related to or rely on the canonical stop codon-dependent translation termination machinery involving class-1 release factors RF1 and RF2 ( 2 , 3 ). While alternative rescue factor A (ArfA) recruits RF2 to release the stalled polypeptide in the absence of the A-site stop codon ( 10 ), ArfB acts as a peptidyl hydrolase itself ( 11 ).…”

Quality Control Mechanisms in Bacterial Translation

“…The ribosome with a free A site serves as a substrate for tmRNA and ArfA; a similar arrangement was suggested for ArfB, but ArfB was found to interact with ribosomes even when a small mRNA segment extends from the P site [ 34 ]. In this situation, the nucleotides of the decoding center are re-arranged, which leads to the expansion of the mRNA tunnel.…”

Widespread ribosome stalling in a genome-reduced bacterium and the need for translational quality control

“…If stalled ribosomes accumulate in the cell, the ribosome pool can be rapidly depleted, subsequently leading to cell death. To solve this problem, bacteria have evolved ribosome rescue pathways to release the nascent peptide and recover the ribosomes for further cycles of translation ( Keiler, 2015 ; Buskirk and Green, 2017 ; Huter et al, 2017 ; Müller et al., 2021 ).…”