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

Descripción del proyecto

La función de las proteínas de transferencia de lípidos en la compartimentalización y el metabolismo lipídicos

Las membranas plasmáticas de las células eucariotas presentan un composición lipídica heterogénea, lo que favorece la segregación de procesos biológicos diferentes y el enriquecimiento específico de proteínas estructurales, enzimáticas y señalizadoras. El enriquecimiento lipídico diferencial es el resultado de la síntesis y degradación compartimentalizadas de lípidos, así como del transporte de lípidos entre membranas a través de las proteínas de transferencia de lípidos (PTL, o LTP por sus siglas en inglés), que facilitan el transporte no vesicular de lípidos a través de espacios acuosos. Aún se desconoce la función de la mayoría de las PTL, las cargas lipídicas y los orgánulos objetivo. El proyecto LipTransProMet, financiado con fondos europeos, tiene por objeto determinar la función de las PTL en el metabolismo lipídico mediante el empleo de líneas celulares con atenuación génica de PTL, junto con métodos de biología de sistemas, como la lipidómica y el análisis térmico de proteomas.

Objetivo

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.