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We found out which subunits of human BBSome complex are critical for development of ciliopathies.
Mutations in any of the eight BBSome subunits can cause Bardet-Biedl syndrome (BBS), a ciliopathic disorder affecting multiple organs due to faulty cilia—tiny cellular antennae that transmit signals. The BBSome structure remained unclear, though studies suggested strong subunit interconnections. Using expansion microscopy and biochemical techniques on genetically engineered human RPE1 cells, we mapped the step-by-step process of BBSome formation. Later, this work was followed by Prasai et al., 2024 showing how the hyperactive ciliary regulator protein contributes to exaggerated ectocytosis, constantly shortening cilia, and resulting in higher BBS disease severity. This study highlights the power of expansion microscopy in surpassing resolution limits and accelerating discoveries in cellular biology.
Primary cilium for mechanosensation
Primary cilium for mechanosensation
The cilium is a specialized, microtubule-based organelle anchored by a basal body and designed for intercellular signaling. Its core, the axoneme, provides "railways" for bidirectional intraflagellar transport (IFT), a process driven by motor proteins. This IFT machinery, which is regulated by the BBSome complex, is essential for moving the cargo required for cell-to-cell communication.
Credit: Chang et al., 2015
Sequential BBSome assembly in humans
Sequential BBSome assembly in humans
Using advanced microscopy on a custom library of human knockout cell lines, we elucidated the sequential mechanism of BBSome assembly. We demonstrated that BBS4 nucleates the pre-BBSome at pericentriolar satellites, followed by BBS1-mediated translocation to the ciliary base, providing a framework for understanding BBS-related mutations.
Find out more in Prasai et al., 2020
Find out more in Prasai et al., 2024
Ectocytosis is sped up in ciliopathy
Ectocytosis is sped up in ciliopathy
We identified that GTPase CDC42 is the key trigger for ciliary ectocytosis in BBSome-deficient cells. We found that Shh signaling amplifies this CDC42 activity, driving actin polymerization that leads to ciliary shortening and shedding. This mechanism, intended to clear cargo like GPR161, appears to be hyperactive in BBS pathology, and we propose that the resulting loss of ciliary material contributes to disease severity.
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