New molecular mechanisms of inter-organelle lipid transport

Abstract

Lipids are precisely distributed in cell membranes, along with associated proteins defining organelle identity. Because the major cellular lipid factory is the endoplasmic reticulum (ER), a key issue is to understand how various lipids are subsequently delivered to other compartments by vesicular and non-vesicular transport pathways. Efforts are currently made to decipher how lipid transfer proteins (LTPs) work either across long distances or confined to membrane contact sites (MCSs) where two organelles are at close proximity. Recent findings reveal that proteins of the oxysterol-binding protein related-proteins (ORP)/oxysterol-binding homology (Osh) family are not all just sterol transporters/sensors: some can bind either phosphatidylinositol 4-phosphate (PtdIns(4)P) and sterol or PtdIns(4)P and phosphatidylserine (PS), exchange these lipids between membranes, and thereby use phosphoinositide metabolism to create cellular lipid gradients. Lipid exchange is likely a widespread mechanism also utilized by other LTPs to efficiently trade lipids between organelle membranes. Finally, the discovery of more proteins bearing a lipid-binding module (SMP or START-like domain) raises new questions on how lipids are conveyed in cells and how the activities of different LTPs are coordinated.

Advances on the Transfer of Lipids by Lipid Transfer Proteins

“…Nevertheless, more detailed studies are required to determine whether the production rate of PIPs can match the required lipid transfer rate. The model has raised the importance of considering second lipids for LTPs other than ORPs [41]. Other LTPs with second lipids that might engage in countercurrent include alpha-tocopherol transfer protein among other Sec14 homologues 42, 43 and RdgB/Nir 44, 45, where PI is likely to be the lipid under metabolic control.…”

Molecular basis for sterol transport by St ART ‐like lipid transfer domains

“…As a result, organelles differ in the composition of their lipid bilayers, imparting different biochemical and biophysical characteristics and helping to define organelle identity (Bigay & Antonny, ). Membrane contact sites, where two organelles are closely apposed, and the lipid transfer proteins enriched at such sites play critical roles in lipid redistribution (Lahiri et al , ; Drin et al , ; Kentala et al , ; Reinisch & De Camilli, ; Saheki et al , ). By definition, lipid transport proteins include lipid binding modules which function by solubilizing lipids during transit across the cytosol between two organelle membranes.…”

“…Some transport proteins additionally serve as tethers, helping to maintain the architecture of contact sites. Identification and characterization of lipid transporters at membrane contact sites are an area of ongoing research critical in unraveling the mechanisms that underlie lipid homeostasis (Schauder et al , ; Lahiri et al , ; Drin et al , ; Kentala et al , ; Reinisch & De Camilli, ; Saheki et al , ; Lees et al , ).…”

Direct trafficking pathways from the Golgi apparatus to the plasma membrane

“…However, GOLPH3 has also been shown to specifically bind and recycle a subset of Golgi enzymes involved in glycan assembly on sphingolipids [180]. This role of GOLPH3 matches the role of its yeast homolog Vps74 which binds to PI(4)P at the trans-Golgi and interacts with specific Golgi enzymes allowing their retrograde transport [181,182]. 7.3 Lipid transport proteins PI(4)P recruits a range of lipid transport proteins (reviewed in [183][184][185]), such as FAPP2, oxysterol-binding protein (OSBP), and ceramide transfer protein (CERT). These proteins share a similar domain organisation: an N-terminal PH domain that binds PI(4)P (and simultaneously Arf1-GTP for OSBP and FAPP2), a C-terminal FFAT motif that binds the ER membrane protein VAP and a C-terminal lipid transport domain.…”