Journal
CURRENT BIOLOGY
Volume 32, Issue 13, Pages 2821-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2022.04.089
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Funding
- MRC [MC_PC_17135]
- SFC [H17007]
- Wellcome Trust Technology Platform'' award [097945/B/11/Z]
- Wellcome Trust [211193/Z/18/Z]
- Royal Society [RGS\R2\180284]
- Wellcome Trust [211193/Z/18/Z] Funding Source: Wellcome Trust
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The study reveals the molecular mechanism of exocyst-mediated membrane tethering, showing that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) plays a crucial role in this process. The researchers demonstrate that vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) are rapidly converted to PI(4,5)P-2 through the recruitment of the lipid kinase PIP5K1C, which drives the recruitment of exocyst complex and membrane tethering.
Polarized trafficking is necessary for the development of eukaryotes and is regulated by a conserved molecular machinery. Late steps of cargo delivery are mediated by the exocyst complex, which integrates lipid and protein components to tether vesicles for plasma membrane fusion. However, the molecular mechanisms of this process are poorly defined. Here, we reconstitute functional octameric human exocyst, demonstrating the basis for holocomplex coalescence and biochemically stable subcomplexes. We determine that each subcomplex independently binds to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2), which is minimally sufficient for membrane tethering. Through reconstitution and epithelial cell biology experiments, we show that Arf6-mediated recruitment of the lipid kinase PIP5K1C rapidly converts phosphatidylinositol 4-phosphate (PI(4)P) to PI(4,5)P-2, driving exocyst recruitment and membrane tethering. These results provide a molecular mechanism of exocyst-mediated tethering and a unique functional requirement for phosphoinositide signaling on late-stage vesicles in the vicinity of the plasma membrane.
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