期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 8, 页码 2877-2890出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201710132
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资金
- National Institutes of Health [T32DK007665, F32CA200024, DK025861]
Cancer cells secrete copious amounts of exosomes, and elevated intracellular Ca2+ is critical for tumor progression and metastasis, but the underlying cellular mechanisms are unknown. Munc13-4 is a Ca2+-dependent SNAP receptor-and Rab-binding protein required for Ca2+-dependent membrane fusion. Here we show that acute elevation of Ca2+ in cancer cells stimulated a fivefold increase in CD63(+), CD9(+), and ALIX(+) exosome release that was eliminated by Munc13-4 knockdown and not restored by Ca2+ binding-deficient Munc13-4 mutants. Direct imaging of CD63-pHluorin exosome release confirmed its Munc13-4 dependence. Depletion of Munc13-4 in highly aggressive breast carcinoma MDA-MB-231 cells reduced the size of CD63(+) multivesicular bodies (MVBs), indicating a role for Munc13-4 in MVB maturation. Munc13-4 used a Rab11-dependent trafficking pathway to generate MVBs competent for exosome release. Membrane type 1 matrix metalloproteinase trafficking to MVBs by a Rab11-dependent pathway was also Munc13-4 dependent, and Munc13-4 depletion reduced extracellular matrix degradation. These studies identify a novel Ca2+- and Munc13-4-dependent pathway that underlies increased exosome release by cancer cells.
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