The multi-omics role of lipid transfer proteins in lipid metabolism

Descrizione del progetto

Le proteine di trasporto dei lipidi nella compartimentazione e nel metabolismo lipidici

Le membrane cellulari delle cellule eucariotiche hanno diverse composizioni lipidiche, il che consente la segregazione di diversi processi biologici e un arricchimento specifico delle proteine enzimatiche, strutturali e di segnalazione. L’arricchimento lipidico differenziale deriva dalla sintesi lipidica compartimentalizzata, dalla decomposizione e dal trasporto lipidico tra membrane da parte delle proteine di trasporto dei lipidi (LTP, Lipid Transfer Protein) che agevolano il trasporto non vescicolare di lipidi attraverso spazi acquosi. La modalità di azione della maggior parte delle proteine di trasporto dei lipidi, dei carichi lipidici e degli organuli di destinazione rimane sconosciuta. L’obiettivo del progetto LipTransProMet, finanziato dall’UE, consiste nel chiarire il ruolo delle proteine di trasporto dei lipidi all’interno del metabolismo lipidico, attraverso linee cellulari di knock-out di tali proteine combinate ad approcci di biologia dei sistemi, quali la lipidomica e la profilazione proteomica termica.

Obiettivo

Cellular membranes of eukaryotic cells vary in their lipid composition, which allows segregation of diverse biological processes and specific enrichment of signaling, enzymatic and structural proteins. Differential enrichment of lipids in different membranes stems from compartmentalized synthesis and degradation of lipids, but also from lipid transport between membranes. Lipid transfer proteins (LTPs) facilitate non-vesicular lipid transport through aqueous spaces, and their dysfunction can lead to diseases. They are crucial for many molecular processes because a large part of the proteome depends on membranes for its function. However, for the majority of the more than 100 LTPs in humans, the lipid cargoes, the integration into metabolism, the mode of action, and the targeted organelles remain unknown. The Gavin group recently performed large screens to identify the lipids bound and transported by LTPs, and during my first months in the host lab, I have been involved in the data analysis of these screens.

Our primary objective in the current project is to take the next step by exploring the role of LTPs in lipid metabolism. We will evaluate the effect of LTP knockdown in cell lines with a unique combination of two complementary systems biology approaches: lipidomics and thermal proteome profiling. The integration of these data with previous data from the Gavin group and public databases will highlight lipid metabolic pathways that rely on LTPs for their correct function, and might decipher less obvious connections with other cellular pathways. Moreover, as additional results of this analysis, these data will likely also highlight relevant organelles and maybe even signaling pathways, even further establishing the functions of the LTPs. This project will enhance our insight in the role of non-vesicular transport in lipid metabolism, while the new approach is likely broadly applicable, even for the future study of primary cells from patients.