Biology subjects

DRIN, G.

Publications and source records attributed to DRIN, G..

4 recordsLinked to original sources

bioRxiv2026

Selective MOSPD2-STARD3 interaction at ER contact sites governs late endosome/lysosome dynamics and cholesterol homeostasis

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and other organelles or the plasma membrane play essential roles in lipid exchange and organelle homeostasis; however, how the molecular composition of these sites is functionally specified remains poorly understood. Here, we identify the ER-resident protein MOSPD2 as a novel regulator of late endosome/lysosome (LE/Lys) homeostasis and show that MOSPD2 selectively recruits the cholesterol transporter STARD3 at ER-LE/Lys contacts. Loss of either MOSPD2 or STARD3 leads to an expansion of the LE/Lys compartment, accumulation of free cholesterol at LE/Lys, and impaired LE/Lys fusion dynamics, indicating that both proteins act within a common pathway at ER-LE/Lys contact sites. STARD3 interacts with three members of the MSP-domain protein family, VAP-A, VAP-B and MOSPD2, yet, these tethers are not functionally equivalent at ER-LE/Lys MCSs. Using a series of quantitative binding assays, we show that STARD3 preferentially associates with MOSPD2 rather than with VAP-A or VAP-B, and that neither VAP-A nor VAP-B can compensate for the loss of MOSPD2 to restore LE/Lys biology and cholesterol distribution. This work establishes the MOSPD2-STARD3 complex as a unique functional unit that regulates LE/Lys homeostasis. Collectively, these findings reveal that selective pairing between MSP-domain proteins and their FFAT-containing partners exist and shape the interaction landscape of MCSs to define their functions.

cell biology↗

bioRxiv2025

STARD3 coordinates Endoplasmic Reticulum-late endosome/lysosome contacts and organelle positioning through a GSK3-regulated phosphorylation switch

Membrane contact sites (MCS) are dynamic regions where the membranes of two organelles come into close apposition. MCSs play many roles in cellular homeostasis by facilitating inter-organelle lipid and ion exchange as well as organelle positioning. The late endosome/lysosome (LE/Lys) cholesterol transfer protein STARD3 (StAR-related lipid transfer (START) domain containing protein 3) forms reversible contacts between the LE/Lys and the endoplasmic reticulum (ER). This tether protein contains a Phospho-FFAT motif (two phenylalanines (FF) in an acidic tract (AT)) whose interaction with ER-resident VAP proteins is phosphorylation-dependent. In this study, we identify Glycogen Synthase Kinase 3 (GSK3 and GSK3{beta}) as the kinases responsible for phosphorylating serine 209 within the Phospho-FFAT motif of STARD3. This phosphorylation event is both necessary and sufficient to activate STARD3s tethering activity, thereby promoting ER-LE/Lys contacts. Furthermore, we show that the ER-LE/Lys tethering activity made by STARD3 regulates endosome positioning, revealing an additional function for STARD3 on endosome biology. Our findings establish a direct and critical role for GSK3 in regulating MCS dynamics via STARD3 phosphorylation. This novel insight into GSK3-mediated phosphorylation expands our understanding of the molecular mechanisms governing inter-organelle communication.

cell biology↗

bioRxiv2025

Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities

Lipid transfer proteins (LTPs) are required for the uneven distribution of lipids between cellular membranes, which is essential for many cell functions. In yeast, Osh6 is an LTP that exchanges phosphatidylserine (PS) with phosphatidylinositol 4-phosphate (PI(4)P) between the endoplasmic reticulum (ER) and the plasma membrane (PM), promoting the enrichment of PS in the PM. Here, we address why, to function optimally, Osh6 must bind to Ist2, an ER-resident lipid scramblase able to connect the ER to the PM via an intrinsically disordered region (IDR). We determined in vitro that Osh6 binds to the Ist2 IDR with micromolar affinity, whether empty or bound to its lipid ligands. Moreover, we found that Osh6 efficiently transfers PS at ER-PM contact sites if the Ist2 IDR has a minimal length and its binding site in the IDR is sufficiently removed from the ER surface. Next, we reconstituted the Osh6:Ist2 complex within artificial ER-PM contact sites and demonstrated that the association of Osh6 with Ist2 allows for a fast and directed PS flux between the connected membranes. We identified the Ist2 binding site on the Osh6 surface by validating structural models using our functional assays. Finally, we found that the Osh6-mediated PS transfer can be coupled to the PS scramblase activity of Ist2. These data unveil new functional partnerships between an LTP and a membrane tethering/scramblase protein and point to the general advantage of localizing these processes to membrane contact sites to ensure their efficiency.

biochemistry↗

bioRxiv2022

MOSPD2 a new endoplasmic reticulum-lipid droplet tether functioning in LD homeostasis

Membrane contact sites between organelles are organized by protein bridges. Among the components of these contacts, the VAP family comprises endoplasmic reticulum (ER)-anchored proteins, such as MOSPD2, functioning as major ER-organelle tethers. MOSPD2 distinguishes itself from the other members of the VAP family by the presence of a CRAL-TRIO domain. In this study, we show that MOSPD2 forms ER-LD contacts thanks to its CRAL-TRIO domain. MOSPD2 ensures the attachment of the ER to LDs through a direct protein-membrane interaction involving an amphipathic helix that has an affinity for lipid packing defects present at the surface of LDs. Remarkably, the absence of MOSPD2 markedly disturbs the assembly of lipid droplets. These data show that MOSPD2, in addition to being a general ER receptor for inter-organelle contacts, possesses an additional tethering activity and is specifically implicated in the biology of LDs via its CRAL-TRIO domain.

cell biology↗