Basal body proteins regulate Notch signaling through endosomal trafficking

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Primary cilia and basal body proteins regulate key signaling pathways.
• The specific role of these proteins in Notch signaling remains largely unknown.

Purpose of the Study:

• To investigate the function of Bardet-Biedl syndrome (BBS) proteins in Notch signaling.
• To elucidate the mechanism by which BBS proteins influence Notch receptor trafficking and activity.

Main Methods:

• Utilized zebrafish reporter lines and human cell lines to assess Notch-directed transcription.
• Examined Notch receptor localization at the plasma membrane and cilia.
• Investigated genetic interactions with endosomal trafficking genes (e.g., TSG101) in Drosophila models.
• Analyzed receptor accumulation in endosomes, recycling, and lysosomal degradation.

Main Results:

• Loss of BBS1 or BBS4 leads to increased Notch-directed transcription.
• Notch receptor localization is reduced at the plasma membrane and cilium in BBS mutants.
• BBS proteins genetically interact with the ESCRT pathway, causing receptor accumulation in late endosomes.
• Disruption of BBS1, BBS4, BBS3, and ALMS1 affects Notch receptor endosomal trafficking, recycling, and degradation.

Conclusions:

• Bardet-Biedl syndrome proteins play a critical role in regulating Notch signaling.
• These proteins mediate Notch receptor trafficking through the endosomal pathway.
• Defects in BBS proteins disrupt normal endosomal processing of the Notch receptor, leading to pathway dysregulation.