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A-to-I mRNA editing in bacteria can affect protein sequence, disulfide bond formation, and function.

ABSTRACT: Adenosine-to-inosine (A-to-I) mRNA editing can alter genetic information at the RNA level and is known to affect protein sequence and function in eukaryotes. However, the ability of A-to-I mRNA editing to recode protein sequences in bacteria was never shown at the protein level. Furthermore, the effect of A-to-I mRNA editing itself-not by A-to-G DNA-mimicking mutations-on protein function was never demonstrated in bacteria. Here, we show at the RNA and protein levels that A-to-I mRNA editing directly recodes a tyrosine to a cysteine residue in the toxin HokB (part of the HokB/sokB toxin-antitoxin system in Escherichia coli). Consequently, the toxicity of edited HokB increases, inducing bacterial death or early entrance into the stationary phase, depending on its expression level. Furthermore, we demonstrate that in vivo disulfide bond formation underlies the effect of A-to-I mRNA editing on HokB function, suggesting that A-to-I mRNA editing constitutes a novel mechanism to regulate disulfide bond formation in bacteria. Finally, we observe that A-to-I mRNA editing of hokB is conserved in pathogenic bacteria, supporting functional importance with possible clinical relevance. Our work reveals that A-to-I mRNA editing can constitute a novel mechanism to regulate protein sequence, disulfide bonds, and function in bacteria.

SUBMITTER: Didi L

PROVIDER: S-EPMC12214031 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature

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A-to-I mRNA editing in bacteria can affect protein sequence, disulfide bond formation, and function.

Didi Liron L Fargeon Ofir O Aspit Liam L Elias Eyal E Braverman Dor D Melamed Dganit D Keidar-Friedman Daniel D Sorek Nadav N Raz Orit O Tamir Sharon Ovnat SO Zarivach Raz R Sal-Man Neta N Dahan Orna O Pilpel Yitzhak Y Bar Yaacov Dan D

Nucleic acids research 20250601 12

Adenosine-to-inosine (A-to-I) mRNA editing can alter genetic information at the RNA level and is known to affect protein sequence and function in eukaryotes. However, the ability of A-to-I mRNA editing to recode protein sequences in bacteria was never shown at the protein level. Furthermore, the effect of A-to-I mRNA editing itself-not by A-to-G DNA-mimicking mutations-on protein function was never demonstrated in bacteria. Here, we show at the RNA and protein levels that A-to-I mRNA editing dir ...[more]

PMID: 40598894

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Project description:The protein secretory pathway must maintain homoeostasis while producing a wide assortment of proteins in different conditions. It is also used extensively to produce many useful proteins in biotechnology. As such, secretory pathway dysfunction can be highly detrimental to the cell, resulting in the molecular basis for many human diseases, and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. To better understand some of these dysfunctions, we measured multiple systems-level states of the cell (physiology, transcriptome, metabolism) while secreting a small protein (insulin precursor) or a large protein (?-amylase). This was carried out in the presence and absence of HAC1, a key transcription factor in maintaining secretory homeostasis. Clear trends in cellular stress were apparent across multiple data resulting from our perturbations. In particular, processes involving (1) degradation of protein / recycling amino acids, (2) overall transcription/translation repression, and (3) oxidative stress. Apparent runaway oxidative radical production was explained by a thermodynamic model that we put forward for disulfide formation in the endoplasmic reticulum. This model predicts that balancing the relative rates of protein folding and disulfide bond formation are key to easing oxidative stress. These predictions have direct implications in how to engineer a broad range of recombinant proteins for secretion and provide potential hypotheses for the root causes of several secretory-associated diseases. Yeast strains were constructed that produce and secrete (a) IP or (b) ?-amylase and were compared to yeast strains containing (c) an empty vector in both wild-type and HAC1 deletion backgrounds. These strains are named WN (WT with empty vector), WI (WT secreting IP), WA (WT secreting ?-amylase), dN (?hac1 with empty vector), dI (?hac1 secreting IP), and dA (?hac1 secreting ?-amylase). Strains were characterized in batch fermentation and samples were taken in mid-exponential phase. Triplicate fermentations were carried out for each strain.

Dataset Information

A-to-I mRNA editing in bacteria can affect protein sequence, disulfide bond formation, and function.

Publications

A-to-I mRNA editing in bacteria can affect protein sequence, disulfide bond formation, and function.

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