zhou, t. | bioRxiv Science

bioRxiv2025

BLTP2 orchestrates lysobisphosphatidic acid synthesis and exosome biogenesis via SCAMP3-dependent ER contacts in tumorigenesis

Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes for cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer protein 2 (BLTP2; KIAA0100) is indispensable in ILV/exosome formation and that secretory carrier membrane protein 3 (SCAMP3) recruits BLTP2 to ER-MVB membrane contact sites (MCSs) in a Rab5-dependent manner. Our results indicate that this recruitment is hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion of BLTP2 was found to impede ILV/exosome formation and selectively diminish the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP) and the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored to a significant extent by supplementation with exosomes from wild-type cells. Since BLTP2 is associated with acute monocytic leukemia and is highly expressed in breast cancer, our findings suggest that BLTP2 transfers the BMP/LBPA precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs, a process crucial for cell proliferation and tumorigenesis.

cell biology↗

bioRxiv2024

Sec14L6 is a PS and PI4P transporter that promotes lipid droplet formation

Lipid droplets (LDs) are evolutionarily conserved organelles that are crucial for cellular metabolism. LD biogenesis and growth occurs in the ER and requires the supply of phospholipid from the ER, but the molecular basis is largely unclear. Here, we have identified Sec14L6, a unique protein of the Sec14 family, as a PS/PI4P transporter required for LD biogenesis. Sec14L6 knockout (KO) greatly reduces the number of LDs that can be rescued by wild-type rather than lipid transfer-defective Sec14L6 mutants. We found that Sec14L6 directly interacts with ACSL3, and that this interaction facilitates targeting of Sec14L6 to LDs and activates the PS transfer activity of Sec14L6 in vitro. We also identified PGRMC1, an ER membrane protein, as an adaptor that recruits Sec14L6 to the ER. Furthermore, depletion of Sec14L6 impairs differentiation of adipose-derived mesenchymal stem cells. Together, our study suggests that Sec14L6 transports PS and/or PI4P between the ER and LDs to promote LD formation.

cell biology↗