Basal body proteins regulate Notch signaling via endosomal trafficking

Abstract

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 the Bardet-Biedl syndrome proteins BBS1 or BBS4 produces increased Notchdirected transcription in a zebrafish reporter line and in human cell lines. Pathway overactivation is 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 observe genetic interaction of BBS1 and BBS4 with the endosomal sorting complexes required for transport (ESCRT) gene TSG101 and accumulation of receptor in late endosomes, reduced endosomal recycling and reduced receptor degradation in lysosomes. We observe similar defects with disruption of BBS3. Loss of another basal body protein, ALMS1, also enhances Notch activation and the accumulation of receptor in late endosomes, but does not disrupt recycling. These findings suggest a role for these proteins in the regulation of Notch through endosomal trafficking of the receptor.

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

“…However, in this context depletion of ciliary proteins resulted in the upregulation of the Notch pathway . In line with these results, disruption of IFT in the pancreas and in zebrafish tissues also abnormally increased Notch activity, suggesting a context-specific role of the cilium on Notch signaling (Cervantes et al, 2010;Leitch et al, 2014;Liu et al, 2014).…”

“…The freed NICD translocates to the nucleus where it activates target genes such as those encoding the Hes and Hey transcription factors, which in turn affect numerous pathways involving cell fate determination. The involvement of primary cilium in the regulation of Notch pathway, however, is debated mostly owing to contradictory findings in ciliary mutants, ranging from inactivation to overactivation of the pathways (Cervantes et al, 2010;Ezratty et al, 2011;Leitch et al, 2014;Liu et al, 2014).…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…A more generalized role in intracellular transport is an example of this since the effect of disrupting the BBS proteins might affect trafficking of proteins destined to other regions of the plasma membrane, to a given organelle, or that depend on the endosomal and secretory pathways for their function as it has been shown for Notch [83]. The possible shuttling of BBS proteins in and out of the nucleus provides another means by which these proteins could modulate signaling for example.…”

“…Several BBSome components have been involved in retrograde, dynein-mediated, melanosome transport in zebrafish, a process that is not linked to cilia [82]. BBS1 and BBS4 recycle the Notch receptor to the plasma membrane [83]. This receptor is present both at the plasma and ciliary membrane, and it is internalized after activation.…”

“…When levels of BBS1 or BBS4 are reduced, recycling of Notch from early endosomes is diminished, suggesting that the BBS proteins participate in the trafficking from early endosomes to the cell surface ( Fig. 3A; [83]). The ciliary pocket appears as a privileged site for vesicle docking [85], so it is possible that recycling to the plasma membrane occurs at this site and receptors are then distributed to the rest of the cell surface.…”