Biology subjects

Metatla, I.

Publications and source records attributed to Metatla, I..

3 recordsLinked to original sources

bioRxiv2026

Serum Proteomics Profiling in Newborns: Differences Compared to Adults serum and new molecular markers for neonatal Sepsis

BackgroundNeonatal sepsis is a major cause of morbidity and mortality, particularly in low- and middle-income countries such as Senegal, where incidence is 78-104 per 1,000 live births and mortality exceeds 20 per 1,000, with case fatality rates around 36%. Diagnosis is difficult due to non-specific clinical signs and lack of molecular biomarkers, highlighting the need for improved early diagnostic molecular markers that could be applied even outside of hospital settings. ObjectivesCompare neonatal and adult serum proteomes to establish a reference and identify serum protein biomarkers of neonatal sepsis. MethodsSerum samples from Senegalese neonates and adults were analyzed using data-independent acquisition (DIA) proteomics on neat serum (Evosep-timsTOF HT platform). The cohort comprised 6 neonates with non-confirmed sepsis (NCS), 22 with confirmed sepsis (CS), 17 healthy newborn controls (HC), 6 unclassified and 20 healthy adults. Downstream analyses included differential protein abundance testing, unsupervised clustering, weighted gene co-expression network analysis (WGCNA), and correlation analyses with clinical parameters. ResultsWe identified 979{+/-}20 proteins in newborns versus 718{+/-}40 in adults. Newborns showed reduced immune-response proteins, a narrower dynamic range, and increased structural proteins such as collagens, consistent with immune immaturity and tissue development. Unsupervised WGCNA analysis led to a 53-protein cluster discriminated CS from NCS/HC. Some of these dysregulated proteins identified have already been reported in independent studies using different approaches in neonatal and/or adult sepsis. Our larger panel however of identified markers maps to three major biological processes involved in sepsis: (i) pathogen sensing (LBP, CD14), and acute-phase inflammation (e.g. CRP, SAA1/2, ORM1/2); (ii) innate immune activation and leukocyte recruitment (e.g., FCGR3A, CSF1R, CD163, CD206) and final platelet exhaustion and metabolic dysregulation, (e.g., PF4, PPBP, THBS1, GP5); (iii) endothelial injury and microvascular dysfunction with tissue remodeling (e.g., ICAM1, VCAM1, VWF, SPARC) and loss of protective lipoproteins and serpins (e.g., APOA1, APOA2, APOM, SERPINA4, SERPINA5) ConclusionThis study provides a very comprehensive neonatal serum proteome characterization and identifies, for the first time, a protein panel of proteins mapped to three major processes in sepsis.

pathology↗

bioRxiv2023

Characterization of the Plasmodium berghei regulatory AAA-ATPase subunit Rpt3 as an activator of Protein Phosphatase 1: direct and indirect evidence

The 26S proteasome is the main proteolytic machine involved in protein degradation, thus contributing to homeostasis or stress response of eukaryotic cells. This macromolecular complex, consisting of a 20S core particle assembled with one or two 19S regulatory particles, is highly regulated by phosphorylation. Here we describe the Plasmodium berghei proteasome AAA-ATPase regulatory subunit Rpt3 and show that it binds to protein phosphatase 1, the major parasite phosphatase. In addition, PbRpt3 regulates the activity of the phosphatase both in vitro and in a heterologous model of Xenopus oocytes. Using mutagenesis approaches, we observed that the RVXF motifs of PbRpt3 are involved in this binding and activity. Further use of Xenopus oocyte model and mutagenesis based on the 3D model that we established revealed that the binding capacity of PbRpt3 to ATP may also contribute to its phosphatase-regulating activity. In the parasite, reverse genetic studies suggested an essential role for PbRpt3 since no viable knock-out line could be obtained. Additionally, immunoprecipitation assays followed by mass spectrometry analyses using transgenic PbRpt3-tagged parasites not only confirmed that PbRpt3 belongs to the 19S regulatory particle of the proteasome, but also revealed potential interaction with proteins already shown to play a role in the phospholipid membrane dynamics.

microbiology↗

bioRxiv2023

Characterization of GEXP15 as a potential regulator of Protein Phosphatase 1 and partner of ribosomal complex in Plasmodium falciparum.

The Protein Phosphatase type 1 catalytic subunit (PP1c) (PF3D7_1414400) operates in combination with various regulatory proteins to specifically direct and control its phosphatase activity. However, little is known about this phosphatase and its regulators in the human malaria parasite, Plasmodium falciparum. To address this gap, we conducted a comprehensive investigation into structural and functional characteristics of a conserved Plasmodium-specific regulator called Gametocyte EXported Protein 15, GEXP15 (PF3D7_1031600). Through in silico analysis, we identified three significant regions of interest in GEXP15: an N-terminal region housing a PP1-interacting RVxF motif, a conserved domain whose function is unknown and a GYF-like motif that potentially facilitates specific protein-protein interactions. To further elucidate the role of GEXP15, we conducted in vitro interaction studies, which demonstrated a direct interaction between GEXP15 and PP1 via the RVxF binding motif. This interaction was found to enhance phosphatase activity of PP1. Additionally, utilizing a transgenic GEXP15-tagged line and live microscopy, we observed high expression of GEXP15 in late asexual stages of the parasite, with localization predominantly in the parasite nucleus. Immunoprecipitation assays followed by mass spectrometry analyses revealed GEXP15s interaction with ribosomal and RNA binding proteins. Furthermore, through pulldown analyses of recombinant functional domains of GEXP15 tagged with a His-tag, we confirmed its binding to the ribosomal complex via the GYF domain. Collectively, our study sheds light on the PfGEXP15-PP1-ribosome interaction, which plays a crucial role in protein translation. These findings suggest that PfGEXP15 could serve as a potential target for the development of malaria drugs.

microbiology↗