Biology subjects

Ferreira, B.

Publications and source records attributed to Ferreira, B..

8 recordsLinked to original sources

bioRxiv2025

Coexistence of two divergent TprA/PhrA cell-cell communication systems in Streptococcus mitis coordinate bacteriocin production, competence, oxidative stress responses, and interspecies competition with S. pneumoniae

Cell-cell communication (CCC) systems are key regulators of bacterial behaviors and adaptation. The human upper respiratory tract is co-colonized by commensal and pathogenic streptococci, but how CCC systems mediate their interactions remains unclear. Here, we investigated the TprA/PhrA quorum-sensing system, composed of the transcription factor TprA and its cognate signaling peptide PhrA, across Streptococcus mitis and S. pneumoniae. Comparative genomics showed that this system is broadly distributed across both species, with most strains sharing identical phrA alleles that enable interspecies signaling. In both species, the tprA/phrA module is commonly linked to the streptococcin E (sce) locus, encoding a putative bacteriocin. We show that activation of the sce operon enhances the competitive fitness of S. mitis in biofilm and infection models. In S. mitis strain C22, two diverse copies of tprA/phrA are present and differentially regulated, coordinating expression of tprA/phrA and the downstream sce locus through both shared and independent pathways. Transcriptomic analyses revealed redundancy, additivity, and cross-regulation between the two systems, linking them to the control of bacteriocin production, competence, and oxidative stress responses. Distinct promoter architectures and TprA-binding motifs underlie the functional divergence of these paralogues, highlighting how regulatory diversification can expand quorum-sensing outputs. Together, our findings show that S. mitis has evolved a flexible and layered communication network that integrates population sensing with antimicrobial and competence responses, providing a molecular basis for its competitive interactions with S. pneumoniae during colonization of the human respiratory tract.

microbiology↗

bioRxiv2025

Network rewiring of a pneumococcal communication system promotes stress adaptation in a globally successful lineage

Cell-cell communication (CCC) systems regulate bacterial behaviors and shape social interactions within microbial communities. In Streptococcus pneumoniae, several CCC systems coordinate intra- and inter-strain signaling, yet the genetic plasticity of their components and regulons remains underexplored. Here, we investigate a divergent allelic variant of the TprA/PhrA CCC system, a regulator-pheromone pair widely conserved in S. pneumoniae. We characterize PhrA1.2, the second most prevalent PhrA pheromone, as a non-signaling variant found in the globally distributed GPSC6 lineage, with presence in isolates dating back to the 1960s. In GPSC6, PhrA1.2 co-occurs with TprA1.2, a truncated transcriptional regulator carrying premature stop codons that eliminate the predicted pheromone-binding domain. Functional assays show that PhrA1.2 is non-functional, both when paired with the truncated TprA1.2 and when paired with the canonical regulator allele TprA1.1. Unexpectedly, despite its truncation, TprA1.2 activates genes involved in oxidative stress responses, including those related to iron-sulfur cluster formation and redox homeostasis. Loss of tprA1.2 impairs growth and increases hydrogen peroxide sensitivity, while in vivo experiments reveal a fitness defect during nasopharyngeal colonization. Together, our findings show that the TprA1.2 allele represents a regulator that has lost its communication component while modifying its regulon. This variant promotes adaptation to oxidative stress and contributes to colonization, demonstrating circuit rewiring of a peptide-regulator CCC system in an epidemiologically relevant S. pneumoniae lineage.

microbiology↗

bioRxiv2025

TRIB2 supports a high glycolytic phenotype in melanoma cells

Metabolic adaptation plays a crucial role in driving the progression of human melanoma contributing to therapy resistance and disease relapse. The pseudo serine/threonine kinase Tribbles homolog 2 (TRIB2) is prominently expressed in melanoma tissue, promoting resistance to anti-cancer treatments and correlating with unfavorable clinical outcomes. Despite this understanding, the impact of TRIB2 expression on melanomas metabolic profile remains unexplored. Here we use UACC-62 melanoma cells which exhibit substantial endogenous expression of TRIB2 as well as engineered isogenic TRIB2 knock out (KO) cells to assess the effect of the loss of TRIB2 on metabolism. Our findings reveal that TRIB2-KO cells display reduced glycolytic activity and heightened vulnerability to pharmacological inhibition of oxidative metabolism, contrasting with the parental cell line. These metabolic and phenotypic changes are driven by TRIB2s coordinated regulation of multiple glycolytic genes, whose combined effect might produce the glycolytic phenotype observed in parental cells. Collectively, our results underscore important role of TRIB2 as a modulator of the metabolic shift implicated in therapy resistance. These insights highlight TRIB2 as a potential target for therapeutic intervention, aiming to counteract the metabolic adaptations driving melanomas resistance mechanisms. HighlightsO_LIMain problem in melanoma is the limited therapy efficacy due to resistance; C_LIO_LITRIB2 is a novel unexplored and druggable target; C_LIO_LITRIB2 expression contributes to increased glycolysis in melanoma cells; C_LIO_LITRIB2 is a driver of a metabolic switch that fuels therapy resistance. C_LI

cancer biology↗

bioRxiv2024

Resistance to Carcinogenesis in the African Spiny Mouse (Acomys) correlates with upregulation of tumor suppressor genes.

Cancer remains a leading cause of morbidity and mortality worldwide, driving extensive research into the mechanisms that contribute to its development and progression. The search for animal models capable of shedding light on mechanisms of cancer resistance has led researchers to explore various rodent species. Among these, the African Spiny Mouse (Acomys sp.) has attracted considerable attention due to its regenerative abilities. In our study, we compared the response of Mus musculus and Acomys dimidiatus mice to treatment with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) combined with the inducer of proliferation 12-O-tetradecanoylphorbol-13-acetate (TPA). While both Acomys and Mus mice experienced carcinogenic damage to their skin cells, mounted proliferative responses and underwent immune cell infiltration, only Mus mice developed tumors, whereas Acomys remained tumor-free. To uncover the molecular mechanisms underlying this resistance, we performed RNA sequencing on tissue samples from both species at baseline and at multiple time points during the carcinogenesis protocol. The data reveal distinctly different transcriptional responses between both species. In particular, Acomys showed massive upregulation of immune related genes, including a set of tumor suppressor genes, while Mus seemed to focus its response on modifying epidermis structure and regulation of the cell cycle. These differences correlated with an increased apoptotic response in Acomys but not Mus. In summary, our study provides compelling evidence that Acomys mice exhibit remarkable resistance to tumor development under DMBA/TPA carcinogen treatment mediated through the upregulation of a range of processes related to immune surveillance.

cancer biology↗

bioRxiv2024

Induction of the ISR by AB5 subtilase cytotoxin drives IFN-I expression in pDCs via STING activation

We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a pro-inflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed new light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.

immunology↗

bioRxiv2024

The inhibition of three distinct signaling pathways eliminates the oncogenic Tribbles homolog 2 from melanoma cells

Tribbles homolog 2 (TRIB2) is one of three members of the Tribbles family of pseudo serine/threonine kinases. It acts as an oncogene whose expression is correlated with tumor progression and therapy resistance in melanoma. TRIB2 has been implicated in conferring resistance to various anti-cancer therapies suggesting TRIB2 as a therapeutic target for resistant tumors. This study explores the pharmacological targeting of TRIB2, revealing several independent routes of pharmacological manipulations. TRIB2 is a short-lived protein stabilized by inhibition of the PI3K/AKT pathway. Conversely, inhibitors of BRAF, MEK and ERK significantly decrease TRIB2 expression by a mechanism that involves transcription. Additionally, Polo-Like Kinases (PLKs) inhibitors significantly reduce TRIB2 protein expression and stability. Strikingly, increasing concentrations of the kinase inhibitor PIK-75 effectively eliminate TRIB2 in melanoma cells surpassing its PI3K inhibitory activity suggesting the destabilizing effect of the inhibition of an unknown kinase. TMT-based proteomics, chemical biology and genetic manipulation revealed CDK12 as the kinase that mediates the destabilizing effect on TRIB2. Overall, we identify three distinct classes of compounds that efficiently eliminate the oncogenic TRIB2 protein from melanoma cells based on different molecular mechanisms and exhibiting 40 to 200 times greater potency than the previously reported afatinib.

cancer biology↗

bioRxiv2024

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on leukemic blastic plasmacytoid dendritic cell neoplasms (BPDCN). VPS34-IN1, however, interferes with plasmacytoid dendritic cells (pDCs) function by blocking the recruitment of serum and glucocorticoid-regulated kinase 3 (SGK3) to endosomes, which is shown to be necessary for Toll-like receptor 7 (TLR7) signaling. In a contrasting parallel, VPS34-IN1 triggers the activation of the stimulator of interferon genes (STING) and significantly enhances pDCs response to the STING agonist 23-cyclic guanosine monophosphate-adenosine monophosphate (23-cGAMP). This cooperative action with VPS34-IN1 leads to strongly increased expression of type-I interferons (IFNs), associated with an alteration of STING degradation and importantly, inhibition of cap-mediated mRNA translation. Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation, notably by compromising the expression of IFIT1/ISG56, a negative regulator of innate signaling. Thus, despite their limited toxicity towards different cancer lines, inhibitors targeting VPS34 and SGK3 may present promising compounds for controlling the expression of type-I IFNs in response to various microbial stimuli and pathological contexts. One-sentence summaryPharmacological inhibition of VPS34 affects multiple signaling pathways downstream of innate immunity receptors and consequently can inhibit or potentiate type-I Interferon induction according to the danger or microbial stimuli received by plasmacytoid DCs.

immunology↗

bioRxiv2021

A cattle graph genome incorporating global breed diversity

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds. To mitigate this issue, we have generated the first assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into the first graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research.

genomics↗