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BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts
Jingru Wang1, Dongchen Li2, Yazhou Liu2
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
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 for 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 reduce the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP), and of the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored by supplementation with exosomes from wild-type cells. Our findings suggest that BLTP2 transfers the BMP/lysobisphosphatidic acid (LBPA) precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs.
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