Research ArticleNotch Signaling

Lgl reduces endosomal vesicle acidification and Notch signaling by promoting the interaction between Vap33 and the V-ATPase complex

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Sci. Signal.  05 Jun 2018:
Vol. 11, Issue 533, eaar1976
DOI: 10.1126/scisignal.aar1976

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Reducing endosome acidification to antagonize Notch signaling

Lethal-2-giant larvae (Lgl) is a tumor suppressor and cell polarity protein that inhibits Notch signaling. Portela et al. found that Lgl inhibited Notch signaling by reducing endosome acidification, which is necessary for the proteolytic processing and activation of Notch. The ability of Lgl to reduce endosome acidification and Notch signaling depended on the vesicle-associated membrane protein Vap33. Lgl physically and genetically interacted with Vap33, which, in turn, interacted with components of the vacuolar ATPase (V-ATPase), a multiprotein complex that drives endosome acidification. Although the precise mechanism has not been elucidated, these findings show that Vap33 inhibits the activity of the V-ATPase and that Lgl inhibits vesicle acidification by activating or stabilizing Vap33 or by promoting the association of Vap33 with the V-ATPase.

Abstract

Epithelial cell polarity is linked to the control of tissue growth and tumorigenesis. The tumor suppressor and cell polarity protein lethal-2-giant larvae (Lgl) promotes Hippo signaling and inhibits Notch signaling to restrict tissue growth in Drosophila melanogaster. Notch signaling is greater in lgl mutant tissue than in wild-type tissue because of increased acidification of endosomal vesicles, which promotes the proteolytic processing and activation of Notch by γ-secretase. We showed that the increased Notch signaling and tissue growth defects of lgl mutant tissue depended on endosomal vesicle acidification mediated by the vacuolar adenosine triphosphatase (V-ATPase). Lgl promoted the activity of the V-ATPase by interacting with Vap33 (VAMP-associated protein of 33 kDa). Vap33 physically and genetically interacted with Lgl and V-ATPase subunits and repressed V-ATPase–mediated endosomal vesicle acidification and Notch signaling. Vap33 overexpression reduced the abundance of the V-ATPase component Vha44, whereas Lgl knockdown reduced the binding of Vap33 to the V-ATPase component Vha68-3. Our data indicate that Lgl promotes the binding of Vap33 to the V-ATPase, thus inhibiting V-ATPase–mediated endosomal vesicle acidification and thereby reducing γ-secretase activity, Notch signaling, and tissue growth. Our findings implicate the deregulation of Vap33 and V-ATPase activity in polarity-impaired epithelial cancers.

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