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Quality Control Mechanisms in Bacterial Translation

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1.	Title	Title of document	Quality Control Mechanisms in Bacterial Translation
2.	Creator	Author's name, affiliation, country	Anastasiia S. Zarechenskaia; Lomonosov Moscow State University; Россия
2.	Creator	Author's name, affiliation, country	Petr V. Sergiev; Skolkovo Institute of Science and Technology; Lomonosov Moscow State University; Lomonosov Moscow State University; Россия
2.	Creator	Author's name, affiliation, country	Ilya A. Osterman; Skolkovo Institute of Science and Technology; Lomonosov Moscow State University; Sirius University of Science and Technology; Россия
3.	Subject	Discipline(s)
3.	Subject	Keyword(s)	translation; bacteria; quality control; termination; trans-translation
4.	Description	Abstract	Ribosome stalling during translation significantly reduces cell viability, because cells have to spend resources on the synthesis of new ribosomes. Therefore, all bacteria have developed various mechanisms of ribosome rescue. Usually, the release of ribosomes is preceded by hydrolysis of the tRNA–peptide bond, but, in some cases, the ribosome can continue translation thanks to the activity of certain factors. This review describes the mechanisms of ribosome rescue thanks to trans-translation and the activity of the ArfA, ArfB, BrfA, ArfT, HflX, and RqcP/H factors, as well as continuation of translation via the action of EF-P, EF-4, and EttA. Despite the ability of some systems to duplicate each other, most of them have their unique functional role, related to the quality control of bacterial translation in certain abnormalities caused by mutations, stress cultivation conditions, or antibiotics.
5.	Publisher	Organizing agency, location	Acta Naturae Ltd
6.	Contributor	Sponsor(s)	RSF grant (20-74-10031)
7.	Date	(DD-MM-YYYY)	27.07.2021
8.	Type	Status & genre	Peer-reviewed Article
8.	Type	Type	Research Article
9.	Format	File format
10.	Identifier	Uniform Resource Identifier	https://actanaturae.ru/2075-8251/article/view/11401
10.	Identifier	Digital Object Identifier (DOI)	10.32607/actanaturae.11401
11.	Source	Title; vol., no. (year)	Acta Naturae; Vol 13, No 2 (2021)
12.	Language	English=en	ru
13.	Relation	Supp. Files	Fig. 1. Main causes of translational stalling in a bacterial cell and ways of solving these problems. The figure shows possible causes of translational stalling in a bacterial cell and the tools used by the cell to solve the problems. Left: a non-stop complex formed during translation. This type of substrate is recognized by the factors causing emergency translational termination, followed by the hydrolysis of the peptidyl-tRNA (tmRNA, ArfA, BrfA, ArfB, ArfT). Middle: a ribosome stalled on an intact template. In the case of starvation, this ribosome is stabilized in a hibernation state by Etta; during the passage of a polyproline sequence, EF-P promotes the resumption of translation. Resumption of translation is also provided by EF-4. If this complex is formed under the action of an antibiotic, it can be a substrate for a number of ABC-F proteins, HflX, and, possibly, HflXr. If stalling is caused by a cluster of rare mRNA codons, then the ribosome is likely rescued by ArfB. Right: spontaneous dissociation of ribosomal subunits. The RqcP/H and Hsp15 factors can promote the release of the 50S subunit. (All illustrations are created on BioRender.com) (535KB) doi: 10.32607/20758251-2021-13-2-32-44-2549 Fig. 2. Ribosome rescue by trans-translation. The tmRNA–SmpB complex recognizes the ribosome within a non-stop complex and binds in a free A site. Binding of the tmRNA–SmpB complex in the A site leads to the transfer of a polypeptide chain to the Ala-tmRNA and is accompanied by subsequent translocation of the deacylated tRNA from the P site to the E site and the peptidyl-tmRNA–SmpB from the A site to the P site. Trans-translation continues until s tmRNA stop codon is reached, which is recognized by the canonical termination factor RF1 or RF2, which stops translation and releases the polypeptide with a tmRNA-encoded tag. Further, the polypeptide is recognized by several proteases, including ClpXP, ClpAP, HflB, and Tsp13, which leads to its rapid degradation [3, 11–14] (655KB) doi: 10.32607/20758251-2021-13-2-32-44-2550 Fig. 3. Ribosome rescue by ArfA. ArfA binds at the 3’-end of the mRNA [22] and promotes hydrolysis of the peptidyl-tRNA by RF2 (430KB) doi: 10.32607/20758251-2021-13-2-32-44-2551 Fig. 4. (A) – Model of ribosome rescue by ArfB. ArfB binds to the mRNA tunnel of a stalled ribosome. Once bound, the flexible linker region of the protein allows the N-terminal domain to enter the PTC to release a peptide. Then, the ArfB–ribosome complex dissociates [24]. (B) – Scenario of ribosome rescue by ArfB when the A site is occupied. If an extended mRNA fragment protrudes from the P site, this fragment moves outside the mRNA tunnel into the intersubunit space and is stabilized there by an additional copy of the ArfB protein [35]. In this case, catalytic ArfB hydrolyzes the peptidyl-tRNA. Then, the ArfB–ribosome complex dissociates (366KB) doi: 10.32607/20758251-2021-13-2-32-44-2552 Fig. 5. Possible mechanisms of HflX activity. (A) – HflX binds to a free E site [38]. The stalled peptide in the PTC is a signal for HflX to hydrolyze GTP. Then, HflX cleaves the 70S subunit into the 50S and 30S ribosomal subunits that can later be used in another round of translation. (B) – HflX binds to the A site of a stalled ribosome [39]. The peptide is released by the rescue factor ArfA or ArfB. Then, HflX–GTP binds to the A site and causes dissociation of ribosomal subunits (501KB) doi: 10.32607/20758251-2021-13-2-32-44-2553 Fig. 6. Mechanism of action of the RqcP and RqcH (YabO) proteins. RqcP binds to the 50S subunit and stabilizes tRNA at the P site [44, 45]. RqcH delivers the charged alanine tRNA to the 50S, which occupies a free A site. Further, a polypeptide chain is transferred. Then, RqcP loses its affinity to the ribosome and undergoes a translocation-like movement: in this case, the deacylated tRNA moves to the E site and the peptidyl-tRNA moves to the P site. Later, RqcP rebinds to stabilize the peptidyl-tRNA at the P site. The ribosome-bound RqcH recruits Ala-tRNA. Further, the cycle of this “elongation” can be repeated until the RqcH factor dissociates, and the polypeptide is released. The factor hydrolyzing the peptidyl-tRNA is not exactly known. Probably, it is ArfB (367KB) doi: 10.32607/20758251-2021-13-2-32-44-2554 Fig. 7. Mechanism of action of the EF-P factor. Binding of EF-P stimulates elongation in vivo and in vitro when ribosomes are stalled on polyproline sequences. EF-P binds between the E site and the P site on the 50S subunit in close proximity to the peptidyl-tRNA. EF-P is believed to stabilize a PTC substrate conformation productive for the peptidyl transferase reaction [4] (282KB) doi: 10.32607/20758251-2021-13-2-32-44-2555
14.	Coverage	Geo-spatial location, chronological period, research sample (gender, age, etc.)
15.	Rights	Copyright and permissions	Copyright (c) 2021 Zarechenskaia A.S., Sergiev P.V., Osterman I.A. This work is licensed under a Creative Commons Attribution 4.0 International License.