Cracking the lipidome

Organisms use different types of biological building blocks to perform and regulate all of their functions. These building blocks, which include major biological molecules such as DNA, proteins and lipids, are assembled into cells and variations in their composition and localization are the basis for all biological processes. While biologists have a relatively good general understanding of how DNA and proteins work, we know very little about the functions of lipids.

HFSP Young Investigator Grant holder Ulrike Eggert and colleagues
authored on Thu, 06 February 2014

Historically, lipids have been thought of as components of membrane “bags” whose main function is to surround and physically separate different cellular compartments. However, it has become clear that this view is too simplistic. Cells express 10,000s of different lipids and hundreds of enzymes to regulate their production and transport, and except in a few cases, it has not been clear why cells invest so much energy into making and maintaining such a diverse lipidome. As a comparison, the human genome is thought to include ~20,000 genes, which is a similar order of magnitude, but our understanding of the roles of individual genes is orders of magnitude greater than our understanding of the roles of individual lipids. For example, we did not even know if the lipid composition of cells changes as they go through their most basic function, their replication through the cell cycle. We also did not know the chemical identity of the lipids cells as they go through their replicative cycle.

This paper identifies, for the first time, how lipids change during a basic cellular process, using cell division as an example. We found that cells use exquisite chemical specificity and highly precise regulation of their lipid composition and localization as they go through the division process, suggesting that these lipids have much more complex functions that just being part of a passive cellular barrier. The main possible functions of lipids could be two-fold: they could work together with other cellular building blocks to transmit signals and/or they could have mechanical roles, for example by stabilizing different membrane curvatures. Our work proposes that both these roles are important during cell division. For example, in collaboration with the lab of Dr. Sergi Garcia-Mayes at King’s College London, we show that the mechanical properties of lipids from dividing cells are different than in non-dividing cells.

The work that led to this paper was funded largely by an HFSP Young Investigator Grant. The overall aim of the grant was to identify how lipids change in cell division and to develop new tools to study their potential cellular functions. The teams, involved in the grant, led by Aurélien Roux in Geneva and Kaori Sakurai in Tokyo are developing tools and assays to analyze lipid mechanisms in cell division, including the lipids identified in this paper.

More broadly, this work has implications for our understanding of both basic biology and of diseases. In basic biology, lipids are one of the key building blocks of cells, but we are decades behind proteins and DNA in understanding how they work and why they are produced. This paper is one of the first attempts to systematically address these major outstanding questions. Many diseases, e.g., cardiovascular disease (cholesterol is a lipid) and different cancers have been associated with changes in lipid behavior, but we do not know well how to exploit this angle for therapy because we do not well understand how lipids work. To this end, the results of this study increase our basic understanding of lipid function in cells and therefore should pave the way for future therapeutic efforts.

Reference

Dividing Cells Regulate Their Lipid Composition and Localization. Atilla-Gokcumen GE, Muro E, Relat-Goberna J, Sasse S, Bedigian A, Coughlin ML, Garcia-Manyes S, Eggert US.  Cell. 2014 Jan 22. pii: S0092-8674(13)01549-3. doi: 10.1016/j.cell.2013.12.015. [Epub ahead of print]

Pubmed link