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Basal body proteins regulate Notch signaling via endosomal trafficking

2014; The Company of Biologists; Linguagem: Inglês

10.1242/jcs.130344

1477-9137

Carmen C. Leitch, Sukanya Lodh, Victoria Prieto-Echagüe, José L. Badano, Norann A. Zaghloul,

Developmental Biology and Gene Regulation

Proteins associated with primary cilia and basal bodies mediate numerous signaling pathways, but little is known about their role in Notch signaling. Here we report that loss of Bardet-Biedl syndrome proteins, BBS1 or BBS4, produced increased Notch-directed transcription in a zebrafish reporter line and in human cell lines. Pathway overactivation was accompanied by reduced localization of Notch receptor at both the plasma membrane and the cilium. In Drosophila mutants, overactivation of Notch can result from receptor accumulation in endosomes and recent studies implicate ciliary proteins in endosomal trafficking, suggesting a possible mechanism by which overactivation occurs in BBS mutants. Consistent with this, we observed genetic interaction of BBS1/4 with the ESCRT gene TSG101 and accumulation of receptor in late endosomes, reduced endosomal recycling and reduced receptor degradation in lysosomes. We observed similar defects with disruption of BBS3. Loss of another basal body protein, ALMS1, also enhanced Notch activation and accumulation of receptor in late endosomes, but did not disrupt recycling. These findings suggest a role for these proteins in regulation of Notch via endosomal trafficking of the receptor.