Protein targeting determinants to lipid droplets – MOBIL

Lipid droplets (LDs) are the primary organelles regulating cellular lipid fluxes. They play a central role in cellular lipid/energy metabolism and are thus, by essence, directly implicated in a variety of metabolic disorders linked to obesity, such as type II diabetes, cardiovascular diseases, or liver steatosis. Only in recent years, LDs gained deserved focus which led to the identification of many other cellular LD functions such as in neurodegeneration or aging.
LDs morphologically represent unique cellular organelles as they are bounded by a single phospholipid monolayer, as compared to other organelles which have a bilayer membrane. This is because LDs are made by an oil core of neutral lipids, including triglycerides or sterol esters, in an aqueous environment. The phospholipid monolayer of LDs is embedded with proteins that determine the function and fate of LDs in a cell. Controlling LD protein content is therefore critical to lipid metabolism and more generally to LD functions. Indeed, impaired protein localization to the surface of LDs is linked to various lipid-derived disorders including type II diabetes or lipodystrophy. It is thus necessary to understand, at least for medical goals, mechanisms by which proteins specifically localize to the surface of LDs, instead of to bilayer membranes which are much more abundant in the cells.

Because of the oily nature of the LD core, only non-fully transmembrane proteins can bind LDs. Proteins use thus mainly two sequence motifs to bind LDs: hairpins and amphipathic helices. How these motifs specifically target LDs is an important but still unresolved question. MOBIL project focuses on experimentally understanding the consequence of the morphological differences between bilayers and monolayers for protein binding. It develops a pipeline of in vitro tests that will isolate the minimal physicochemical and biophysical parameters necessary for the selective targeting of model hairpins and amphipathic helices to the surface of model LDs over model bilayers. Identifying these parameters will enable to next modulate them in a cellular context to alter protein binding. Such approach can be implemented to any LD protein. Reaching the aim of MOBIL will reveal the basic principles of proteins targeting to LDs and of their function, which will be key to modulating metabolism for medical and industrial avail.