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Heparanase activates the syndecan-syntenin-ALIX exosome pathway
#MMPMID25732677
Roucourt B
; Meeussen S
; Bao J
; Zimmermann P
; David G
Cell Res
2015[Apr]; 25
(4
): 412-28
PMID25732677
show ga
Exosomes are secreted vesicles of endosomal origin involved in signaling
processes. We recently showed that the syndecan heparan sulfate proteoglycans
control the biogenesis of exosomes through their interaction with syntenin-1 and
the endosomal-sorting complex required for transport accessory component ALIX.
Here we investigated the role of heparanase, the only mammalian enzyme able to
cleave heparan sulfate internally, in the syndecan-syntenin-ALIX exosome
biogenesis pathway. We show that heparanase stimulates the exosomal secretion of
syntenin-1, syndecan and certain other exosomal cargo, such as CD63, in a
concentration-dependent manner. In contrast, exosomal CD9, CD81 and flotillin-1
are not affected. Conversely, reduction of endogenous heparanase reduces the
secretion of syntenin-1-containing exosomes. The ability of heparanase to
stimulate exosome production depends on syntenin-1 and ALIX. Syndecans, but not
glypicans, support exosome biogenesis in heparanase-exposed cells. Finally,
heparanase stimulates intraluminal budding of syndecan and syntenin-1 in
endosomes, depending on the syntenin-ALIX interaction. Taken together, our
findings identify heparanase as a modulator of the syndecan-syntenin-ALIX
pathway, fostering endosomal membrane budding and the biogenesis of exosomes by
trimming the heparan sulfate chains on syndecans. In addition, our data suggest
that this mechanism controls the selection of specific cargo to exosomes.
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