Lipid droplet–membrane contact sites – from protein binding to function

Abstract

In the general context of an increasing prevalence of obesityassociated diseases, which follows changing paradigms in food consumption and worldwide use of industry-transformed foodstuffs, much attention has been given to the consequences of excessive fattening on health. Highly related to this clinical problem, studies at the cellular and molecular level are focused on the fundamental mechanism of lipid handling in dedicated lipid droplet (LD) organelles. This Review briefly summarizes how views on LD functions have evolved from those of a specialized intracellular compartment dedicated to lipid storage to exerting a more generalized role in the stress response. We focus on the current understanding of how proteins bind to LDs and determine their function, and on the new paradigms that have emerged from the discoveries of the multiple contact sites formed by LDs. We argue that elucidating the important roles of LD tethering to other cellular organelles allows for a better understanding of LD diversity and dynamics.

Neutral lipids regulate amphipathic helix affinity for model lipid droplets

“…1 I). In cells, additional regulatory means can control the recruitment of AHs (Kory et al, 2016; Thiam and Dugail, 2019). For example, crowding of the LD surface by strongly bound proteins, such as Perilipin 1, or hairpin-containing proteins, enables prevention of the nonspecific adsorption of soluble AH-containing proteins (Ajjaji et al, 2019; Kory et al, 2015).…”

“…This AH has a poorly developed hydrophobic face that needs the presence of charged PLs to reveal its ability to target to membrane packing defects (Pranke et al, 2011). AH–AH interactions, or AH interactions with other LD proteins, may also improve the binding selectivity (Kory et al, 2016; Thiam and Dugail, 2019).…”

“…LDs are covered by a single phospholipid (PL) monolayer embedded with proteins, which determine most LD biological functions (Kory et al, 2016). Many of these proteins bind to LDs by using amphipathic helix (AH) domains, motifs that are also capable of targeting bilayer membranes (Bigay and Antonny, 2012; Kory et al, 2016; Thiam and Dugail, 2019). However, despite the fact that bilayer surfaces are much more abundant in cells, many AH-containing proteins achieve to selectively target to the monolayer surface of LDs.…”

“…Decreasing the PL packing density at the monolayer surface of LDs accentuates the contact between hydrophobic and hydrophilic phases, which is favorable for the binding of AHs (Čopič et al, 2018; Prévost et al, 2018; Thiam et al, 2013a). Indeed, AHs are basically surfactants, and their adsorption to hydrophobic–hydrophilic interfaces is favorable for reducing interfacial energies (Thiam and Dugail, 2019). Currently, there is no experimental determination of the PL packing level at the surface of LDs, nor clear understanding of its contribution to the binding of AHs.…”

ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

“…Furthermore, beyond their role in regulating cell survival and death, LDs are increasingly found to act in other cellular processes, including acting as platforms for the assembly of viruses, and modulators of cell signalling (Boulant et al, 2008,Cheung et al, 2010,Sandoval et al, 2014,Welte and Gould, 2017. They also form intimate contacts with ER and mitochondria (Schuldiner andBohnert, 2017,Thiam andDugail, 2019) and act inside the nucleus (Layerenza et al, 2013,Soltysik et al, 2019,Uzbekov and Roingeard, 2013.…”