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Gut colonization by Bacteroides requires translation by an EF-G paralog lacking GTPase activity.

ABSTRACT: Protein synthesis is crucial for cell growth and survival yet one of the most energy-consuming cellular processes. How, then, do cells sustain protein synthesis under starvation conditions when energy is limited? To accelerate the translocation of mRNA-tRNAs through the ribosome, bacterial elongation factor G (EF-G) hydrolyzes energy-rich guanosine triphosphate (GTP) for every amino acid incorporated into a protein. Here, we identify an EF-G paralog-EF-G2-that supports translocation without hydrolyzing GTP in the gut commensal bacterium Bacteroides thetaiotaomicron. EF-G2's singular ability to sustain protein synthesis, albeit at slow rates, is crucial for bacterial gut colonization. EF-G2 is ~10-fold more abundant than canonical EF-G1 in bacteria harvested from murine ceca and, unlike EF-G1, specifically accumulates during carbon starvation. Moreover, we uncover a 26-residue region unique to EF-G2 that is essential for protein synthesis, EF-G2 dissociation from the ribosome, and responsible for the absence of GTPase activity. Our findings reveal how cells curb energy consumption while maintaining protein synthesis to advance fitness in nutrient-fluctuating environments.

SUBMITTER: Han W

PROVIDER: S-EPMC9841332 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Gut colonization by Bacteroides requires translation by an EF-G paralog lacking GTPase activity.

Han Weiwei W Peng Bee-Zen BZ Wang Chunyan C Townsend Guy E GE Barry Natasha A NA Peske Frank F Goodman Andrew L AL Liu Jun J Rodnina Marina V MV Groisman Eduardo A EA

The EMBO journal 20221206 2

Protein synthesis is crucial for cell growth and survival yet one of the most energy-consuming cellular processes. How, then, do cells sustain protein synthesis under starvation conditions when energy is limited? To accelerate the translocation of mRNA-tRNAs through the ribosome, bacterial elongation factor G (EF-G) hydrolyzes energy-rich guanosine triphosphate (GTP) for every amino acid incorporated into a protein. Here, we identify an EF-G paralog-EF-G2-that supports translocation without hydr ...[more]

PMID: 36472247

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Project description:Microbial colonization of the mammalian gut is largely ascribed to the ability to utilize nutrients available in that environment. To understand how beneficial microbes establish a relationship with their hosts, it is crucial to determine what other abilities promote gut colonization. We now report that colonization of the murine gut by the beneficial microbe Bacteroides thetaiotaomicron requires activation of a putative translation factor by the major transcriptional regulator of gut colonization and carbohydrate utilization. To ascertain how this regulator-called BT4338-promotes gut colonization, we identified BT4338-regulated genes and BT4338-bound DNA sequences. Unexpectedly, the gene whose expression was most reduced upon BT4338 inactivation was fusA2, specifying a putative translation factor. We determined that fusA2 activation by BT4338 is conserved in another Bacteroides species and essential for gut colonization in B. thetaiotaomicron because a mutant lacking the BT4338 binding site in the fusA2 promoter exhibited a colonization defect similar to that of a mutant lacking the fusA2 gene. Furthermore, we demonstrated that BT4338 promotes gut colonization independently of its role in carbohydrate utilization because the fusA2 gene was dispensable for utilization of carbohydrates that depend on BT4338 Our findings suggest that microbial gut colonization requires the use of alternative protein synthesis factors.IMPORTANCE The bacteria occupying the mammalian gut have evolved unique strategies to thrive in their environment. Bacteroides organisms, which often comprise 25 to 50% of the human gut microbiota, derive nutrients from structurally diverse complex polysaccharides, commonly called dietary fibers. This ability requires an expansive genetic repertoire that is coordinately regulated to achieve expression of those genes dedicated to utilizing only those dietary fibers present in the environment. Here we identify the global regulon of a transcriptional regulator necessary for dietary fiber utilization and gut colonization. We demonstrate that this transcription factor regulates hundreds of genes putatively involved in dietary fiber utilization as well as a putative translation factor dispensable for growth on such nutrients but necessary for survival in the gut. These findings suggest that gut bacteria coordinate cellular metabolism with protein synthesis via specialized translation factors to promote survival in the mammalian gut.

Project description:Colon cancer development may be initiated by multiple factors, including chronic inflammation, genetic disposition, and gut dysbiosis. The loss of beneficial bacteria and increased abundance of detrimental microbes exacerbates disease progression. Bacteroides plebeius (B. plebeius) is a human gut microbe, and its colon colonization is enhanced by a seaweed-supplemented diet. We found that mice orally administered with B. plebeius and fed a diet containing 1% seaweed developed a unique gut microbial composition. By linear discriminant analysis effect size analysis, we found that B. plebeius colonization increased the abundance of Blautia coccoides and reduced the abundance of Akkermansia sp. and Dubosiella sp. We also showed that colonization of B. plebeius suppressed the colon tumor development induced by azoxymethane/dextran sulfate sodium in specific-pathogen-free mice, coinciding with a reduced abundance of Muribaculaceae sp., Closteridale sp., and Bilophila sp. Moreover, B. plebeius colonization in gnotobiotic mice resulted in enhanced production of selected metabolites, including propionic, taurocholic, cholic, alpha-, and beta-muricholic, as well as ursodeoxycholic acids. Importantly, some of these metabolites show anti-inflammatory and tumor-suppressive effects. We conclude that B. plebeius is able to restructure the gut microbial community and produce beneficial metabolites, leading to inhibition of colitis-associated colon cancer development.IMPORTANCEThis work delves into the pivotal role of gut microbiota in suppressing the progression of colitis-associated colon cancer. By investigating the impact of Bacteroides plebeius that can be colonized in mouse gut by feeding the animal with seaweed diet, we unveil a novel mechanism through which this beneficial bacterium reshapes the gut microbial community and produces metabolites with anti-inflammatory and tumor-suppressive properties. Such findings underscore the potential of harnessing specific microbes, like B. plebeius shown in this study, to modulate the gut ecosystem and mitigate the risk of colitis-associated colon cancer.

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Gut colonization by Bacteroides requires translation by an EF-G paralog lacking GTPase activity.

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Gut colonization by Bacteroides requires translation by an EF-G paralog lacking GTPase activity.

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