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bioRxiv · 10.1101/2025.04.17.649455

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

Ji, W.·wang, j.·Li, D.·liu, y.·zhou, t.·xiong, j.
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Abstract

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.

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Ji, W., wang, j., Li, D., liu, y., zhou, t., xiong, j.. 2025-04-21. BLTP2 orchestrates lysobisphosphatidic acid synthesis and exosome biogenesis via SCAMP3-dependent ER contacts in tumorigenesis. https://doi.org/10.1101/2025.04.17.649455

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