iBB

PI(4,5)P2 is a phospholipid found mostly in the plasma membrane of eukaryotic cells, where it plays a crucial role in processes like vesicle trafficking, cytoskeletal regulation, ion channel function, viral assembly and budding. While most phospholipids show considerable acyl-chain diversity, PI(4,5)P2 lipids are exceptionally enriched in specific acyl-chains, the most frequent composition in mammalian cells being 1-stearoyl-2-arachidonyl (18:0 20:4). The biological functions that call for this specific enrichment are still not fully clear. In a recent paper published in Communications Chemistry, a BSIRG-iBB team led by Fábio Fernandes together with the teams of Dr. Nuno Santos (IMM) and Dr. Manuel Melo (ITQB) identified a previously unreported increase in membrane order upon calcium-dependent PI(4,5)P2 clustering. Remarkably, the interaction of saturated PI(4,5)P2 with calcium culminated in the formation of gel nanodomains for fully saturated PI(4,5)P2, and the formation of these gel domains was abrogated in the presence of 18:0 20:4 polyunsaturated PI(4,5)P2. These results support a role of (18:0 20:4)PI(4,5)P2 in inhibiting the formation of highly ordered PI(4,5)P2 nanodomains in the plasma membrane.

The role of the cell wall in yeast response and tolerance to stress is frequently neglected. A BSRG-iBB research paper just published in Scientific Reports, provides, for the first time, a comprehensive view of the alterations occurring at the cell wall in a yeast population adapting to sub-lethal stress induced by acetic acid. The results reveal changes to the cell wall polysaccharide composition and nanomechanical properties, as well as alterations in the transcript levels of key cell wall biosynthetic genes. This paper reinforces the notion that the adaptive yeast response to acetic acid involves coordinated alterations of the cell wall at the biophysical and molecular levels. The gathered knowledge is important for the design of superior industrial strains and for the efficient control of the deleterious activity of spoilage yeasts, particularly in the Food Industry. This research work is first-authored by the PhD student of the PhD programme in Biotechnology and Biosciences Ricardo Ribeiro (FCT_DP AEM fellowship), performed under the supervision of Isabel Sá-Correia. This collaborative study with Fábio Fernandes (BSIRG-iBB) and Mário S. Rodrigues and his team (BioISI, Faculty of Sciences, ULisboa), is also coauthored by Cláudia Godinho (posdoc researcher) and the PhD student Nuno Bourbon-Melo (FCT_DP BIOTECnico) from the BSRG-iBB team.

The ability of Saccharomyces cerevisiae to overcome the stress induced by cytotoxic compounds depends on the activity of plasma membrane transporters of the ABC superfamily, presumably through the questionable unspecific efflux of multiple drugs and xenobiotic compounds. A recent paper by iBB researchers provides new insights into the biological role of the ABC transporter of the pleiotropic drug resistance family of putative drug efflux pumps Pdr18, proposed to mediate ergosterol incorporation in plasma membrane. Pdr18 expression was found to help cells to counteract acetic acid-induced decrease of plasma membrane lipid order, increase the non-specific membrane permeability and decrease the transmembrane electrochemical potential. Results support the notion that Pdr18-mediated multistress resistance is linked to the status of plasma membrane lipid environment related with ergosterol content and the associated plasma membrane properties. The paper, published in Scientific Reports, results from the PhD project of Cláudia Godinho, advised by Prof. Isabel Sá-Correia from BSRG-iBB in collaboration with Fábio Fernandes and Sandra Pinto from BSIRG-iBB).

p28 is a 28 amino acids peptide derived from the bacterial protein azurin. It possesses cell-penetrating capabilities showing preferential enter in cancer cells. Moreover it has been subject in US to two phase I clinical trials as a anticancer agent. In a recent paper published in Journal of Controlled Release, a iBB team (Garizo AR, Dias TP, Fernandes F, Bernardes N, Fialho AM) together with a i3S/UP team (Castro F, Martins C, Almeida A, Barrias CC, Sarmento B) were able for the first time to fabricate p28-functionalized PLGA nanoparticles (NPs) loaded with the EGFR tyrosine kinase inhibitor gefitinib. The results obtained indicate that these NPs interact preferentially with lung cancer cells due to their decoration with p28 peptide. In vitro cytotoxicity assays demonstrate biological activity of the NPs against lung cancer cancer cells. Finally, in vivo studies demonstrated a great potential of the p28-NPs in enhancing the therapeutic effects of gefitinib.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) stands out from other plasma membrane lipids as one of the most important regulators of membrane-associated signaling events. PI(4,5)P2 is able to engage in a multitude of simultaneous cellular functions that are temporally and spatially regulated through the presence of localized transient pools of PI(4,5)P2 in the membrane. These pools are crucial for the recruitment, activation, and organization of signaling proteins and consequent regulation of downstream signaling. A review published by the PhD student Luís Borges-Araújo (from the Medical Biochemistry and Biophysics Doctoral Program)  and Fábio Fernandes showcases some of the most important PI(4,5)P2 molecular and biophysical properties, as well as their impact on its membrane dynamics, lateral organization, and interactions with other biochemical partners. The review was published in the Molecules Journal and was selected as the cover of the September issue.