Research highlights
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Bacteria use structural imperfect mimicry to hijack the host interactome
To fulfil their function, proteins need to interact with each other forming complexes. Understanding how pathogen proteins bind their host counterparts is important to explain how bacteria can infect, survive and proliferate inside cells. To achieve that, pathogen proteins mimic eukaryote interfaces to interact with the host. However, we discovered that such mimicry is imperfect, and pathogen proteins display particular features that are not found in eukaryotic complexes. This imperfect mimicry would allow pathogen proteins to actively bind to the host targets while preventing deleterious effects on the pathogen network. Indeed, we show that highly connected proteins (hubs) in the host-pathogen networks are mostly isolated in the pathogen network. The existence of imperfect mimicry opens the door to the design of new molecules aimed to target host-pathogen complexes with reduced side effects. Hence, in the long term, our results may lay the foundation of a new class of antimicrobials.
Cells alter their tRNA abundace to regulate protein expression
To determine, whether cells alter tRNA abundance to selectively regulate protein expression we quantified changes in the abundance of individual tRNAs at different time points in response to diverse stress conditions in Saccharomyces cerevisiae. We found that the tRNA pool was dynamic and rearranged in a manner that facilitate selective translation of stress-related transcripts. Through genomic analysis of multiple datasets, stochastic simulations, and experiments with designed sequences of proteins with identical amino acids but altered codon usage, we showed that changes in tRNA abundance affected protein expression independently of factors such as mRNA abundance.
These observations have a number of important clinical implications. On the one hand, altering the abundance of tRNA could cause anomalous progression of the cell cycle, leading to proliferative diseases such as cancer. In fact, overexpression of tRNAiMet and Brf1, a transcription factor of the RNA polymerase III, causes the formation of tumors in vivo. On the other hand, tRNA has also been related to apoptosis and cell death. It has been shown that tRNA can bind to the cytochrome c that prevents the activation of caspases. Therefore, the levels of tRNA in the cell could also play a relevant role in cellular responsiveness to apoptotic stimuli.
Centrality in the host-pathogen interactome
The idea that protein-protein interactions modulate many, if not most, biological processes is clearly emerging as an exciting and pervasive concept in Biology. In this context, understanding how pathogens interact with its host and how these interactions influence the outcome of infection is an area of intense research.
In a recent paper, we show that proteins with a high impact on pathogen fitness make a higher number of interactions with host proteins. In more specific words, we found that the centrality-lethality rule holds for infection but only when the host-pathogen interactome is considered. We also observed that pathogen proteins that cause an extensive rewiring of the host network have a higher impact on fitness.
Overall, our discoveries show that pathogen fitness is correlated with the connectivity in the host-pathogen interactome. These findings have wide implications in Biology because they provide a mechanistic way to understand the correlation between pathogen genotypes (having or not a particular protein) with a relevant phenotype (being or not able to infect the host).
