June 2nd, 2024

Recent Publications Harnessing the Power of Translatomics.

Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.

In this week’s Sunday papers, Pilling et al. investigate differences in mRNA and protein profiles between male and female neutrophils, revealing variations that could explain disparities in disease prevalence and immune response effectiveness. Böttcher et al. explore the role of the tRNA-modifying enzyme Hma1 in Candida albicans and Candida dubliniensis, highlighting its impact on fungal pathogenicity and response to environmental changes. Finally, Schumacher et al. look at how E. coli modulates gene expression related to motility in response to acid stress.

Differences between human male and female neutrophils in mRNA, translation efficiency, protein, and phosphoprotein profiles

Preprint, 2024

Pilling, D., Consalvo, K.M., Kirolos, S.A. and Gomer, R.H.

Males and females differ in the prevalence of neutrophil-related diseases like systemic lupus erythematosus and rheumatoid arthritis, as well as in neutrophil response to the chemorepellent SLIGKV. The basis for these sex-based differences remains poorly understood. This study investigated these differences by analysing messenger RNA (mRNA) and protein espression levels in neutrophils from healthy humans of both sexes.

The study utilised polysome profiling and subsequent RNA-seq to assess differences in mRNA translation across sexes, identifying variations in translation efficiency. In male neutrophils, at least 16 mRNAs, primarily encoding RNA binding proteins, were more actively translated, whereas female neutrophils showed higher translation rates in 8 mRNAs, 3 of which encode cytoskeletal binding proteins. Protein analysis highlighted distinct disparities with males exhibiting higher levels of 132 proteins, mainly involved in RNA regulation, ribosomal function, and signaling pathways. Females, on the other hand, had an increased presence of 30 proteins, primarily associated with metabolic and proteolytic pathways. Additionally, phosphorylation levels, a key post-translational modification for cellular function, varied significantly. Following exposure to the chemorepellent SLIGKV, male neutrophils exhibited a pronounced increase in the phosphorylation of 32 proteins, a response not mirrored in female neutrophils. This aligns with the faster physiological responses previously observed in male neutrophils, suggesting a sex-based differentiation in neutrophil reactivity and functional readiness.

In conclusion, male neutrophils exhibit increased protein levels and phosphorylation related to RNA processing and signaling, suggesting they adapt more readily to new environments. Conversely, female neutrophils have more proteins linked to metabolism and pathogen response, potentially explaining sex-based disparities in neutrophil behavior and disease outcomes.

A highly conserved tRNA modification contributes to C. albicans filamentation and virulence

Microbiology spectrum, 2024

Böttcher, B., Kienast, S.D., Leufken, J., Eggers, C., Sharma, P., Leufken, C.M., Morgner, B., Drexler, H.C., Schulz, D., Allert, S. and Jacobsen, I.D.

tRNA modifications are crucial for accurate protein synthesis in all life forms and play a complex role in host-pathogen dynamics, especially under the rapid environmental changes typical of infections. This study employed ribosome profiling to investigate the functions of the tRNA-modifying enzyme Hma1 in Candida albicans and Candida dubliniensis, two related fungal pathogens with distinct virulence levels. Hma1 contributes to the production of threonylcarbamoyladenosine in tRNA, influencing fungal growth in the hyphal form which is critical for their pathogenicity.

The deletion of Hma1 in C. albicans was found to disrupt ct6A37 tRNA modification formation and significantly alter ribosome occupancy at 37°C, a key human body temperature. This alteration was found to affect the translation of both canonical and non-ANN codons, including those coding for arginine and histidine, as well as non-canonical start codons (CTG, GTG, TTG), indicating an increase in non-AUG initiation events in the hma1Δ/Δ mutant. Furthermore, ribosome profiling reveals 731 transcripts differentially translated between the hma1Δ/Δ mutant and wild type. In particular, 182 transcripts—involved in filamentation, aggregation, and biofilm formation like ALS1 and HGC1—showed higher ribosome occupancy in the wild type. This underscores Hma1’s role in these processes, while transcripts less abundant in the wild type predominantly relate to metabolic pathways such as lipid oxidation, the glyoxylate cycle, and respiration. 

This research underscores the pivotal impact of tRNA modifications on the virulence and host interaction capabilities of significant human fungal pathogens, with key findings showing that the deletion of HMA1 in C. albicans impairs growth at body temperature and reduces its ability to invade human epithelial cells, ultimately diminishing its virulence in infection models.

Motility-activating mutations upstream of flhDC reduce acid shock survival of Escherichia coli

Microbiology Spectrum, 2024

Schumacher, K., Braun, D., Kleigrewe, K. and Jung, K.


This paper presents a comprehensive analysis of how Escherichia coli, a neutralophilic bacterial species, adapts to varying degrees of acid stress by modulating gene expression linked to motility. Building upon previous research that utilized ribosome profiling to identify changes in gene expression at different pH levels, this study employs RNA sequencing to further dissect the dynamic regulatory responses under acid stress conditions. Specifically, the study investigates the role of FlhDC, the master regulator of flagellar components, and its inverse correlation with acid shock survival, suggesting a trade-off between motility and acid tolerance.

The authors demonstrate that mutations upstream of flhDC enhance motility but reduce survival rates under acid shock. These observations were more pronounced in mutants from the Keio collection which exhibit disrupted flhDC expression due to an insertion sequence element. This study confirms that E. coli differentiates into motile and acid-tolerant subpopulations, depending on the expression levels of motility-related genes and their regulatory networks under stress.

Furthermore, the authors revisited the role of the MhpR, an IclR-type regulator, previously noted for its upregulated expression in severe acid conditions (pH 4.4) and its regulation of metabolic pathways involved in the degradation of aromatic compounds ingested from plant materials. Despite the substantial insights into the transcriptional regulation by MhpR, its specific contributions to acid resistance remain to be fully elucidated. Overall, this paper highlights the complex interplay between environmental stressors and microbial gene regulation, emphasizing the adaptive strategies of E. coli in response to acid challenges in vertebrate gastrointestinal tracts.

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