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Updated: May 1, 2026
Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
Published on: February 21, 2016
Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators
Abstract:
Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients.
Insights
Loss of ciliopathy proteins impairs proteasome function, disrupting paracrine signaling. Augmenting proteasome activity may offer therapeutic benefits for ciliopathy patients.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Cilia are crucial for paracrine signaling.
- Ciliopathies are genetic disorders linked to cilia dysfunction.
- The precise mechanisms by which ciliopathy proteins regulate signaling pathways remain unclear.
Purpose of the Study:
- To investigate if ciliopathy-associated proteins converge on multiple paracrine pathways via a common mechanism.
- To determine the role of proteasomal degradation in ciliopathy-related signaling defects.
- To explore potential therapeutic strategies for ciliopathies by targeting proteasome function.
Main Methods:
- Studied the impact of Bardet-Biedl syndrome 4 (BBS4) and oral-facial-digital syndrome 1 (OFD1) protein loss on signaling mediators.
- Examined interactions between ciliopathy proteins and proteasomal subunits.
- Assessed the effects of proteasome activators (sulforaphane and mevalonolactone) on cellular and organismal models.
- Investigated the influence of ciliopathy protein loss on NF-κB signaling.
Main Results:
- Loss of BBS4 or OFD1 caused accumulation of signaling mediators targeted for proteasomal degradation.
- Ciliopathy proteins interact with proteasomal subunits; their absence depleted centrosomal proteasome components.
- Proteasome activation ameliorated signaling defects in various models (cell lines, zebrafish, mouse neurons).
- Loss of BBS1, BBS4, or OFD1 impaired NF-κB activity, which was rescued by sulforaphane treatment.
Conclusions:
- Basal body proteasomal regulation is a key mechanism governing paracrine signaling pathways.
- Defects in proteasome-dependent pathways are associated with ciliopathies.
- Augmenting proteasomal function presents a potential therapeutic avenue for ciliopathy patients.
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