S008
OSBP: moving cholesterol using the metabolic energy of
phosphoinositides
Bruno Mesmin1, Joëlle Bigay1,
Joachim Moser von Filseck1, Sandra Lacas-Gervais2,
Guilllaume Drin1 and Bruno Antonny1
1
Institute of Pharmacology and Molecular Cell, CNRS,
Valbonne, France
2
CCMA, Nice, France
Vesicular transport necessarily induces the mixing of membranes
of different lipid composition. Without active mechanisms, cellular
organelles that are connected by membrane traffic pathways
would loose their lipid identity. Here we describe a mechanism
that helps to maintain a difference in lipid composition between
two closely apposed organelles. Oxysterol-Binding Protein
(OSBP) contains a PH domain that interacts with the Golgi
phosphoinositide PI(4)P, a FFAT motif that interacts with the
ER protein VAP-A and a lipid transfer domain (e.g. ORD). This
architecture is suggestive of two activities: ER-Golgi tethering to
make a membrane contact site, and lipid transfer. Using cellular
and reconstitution experiments, we show that these two activities
are coupled according to the following cycle: First, membrane
tethering by the PH domain and the FFAT motif enables sterol
transfer by the lipid transfer domain (ORD). Second, the transfer
of sterol is coupled to back transfer of PI(4)P by the ORD. Last,
PI(4)P after its back transfer is hydrolyzed in cis by the ER
protein Sac1. This step makes the cycle irreversible and can drive
forward sterol transfer when the amount of PI(4)P is sufficient
or allow disruption of tethering when PI(4)P becomes limiting.
Because other lipid transfer proteins display a similar architecture, the OSBP cycle might define a general mechanism whereby
the metabolic energy of a phosphoinositide is used to maintain
different levels of other lipid species between apposed organelles.