Unknown

Dataset Information

0

A Ca2+-stimulated exosome release pathway in cancer cells is regulated by Munc13-4.


ABSTRACT: 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.

SUBMITTER: Messenger SW 

PROVIDER: S-EPMC6080937 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC6360358 | biostudies-literature
| S-EPMC6364500 | biostudies-literature
| S-EPMC9437105 | biostudies-literature
| S-EPMC5766930 | biostudies-literature
| S-EPMC5572320 | biostudies-literature
| S-EPMC3488584 | biostudies-literature
| S-EPMC8927349 | biostudies-literature
| S-EPMC8048425 | biostudies-literature
| S-EPMC8452512 | biostudies-literature
| S-EPMC6697748 | biostudies-literature