An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling

Area of Science:

• Cell biology
• Molecular signaling
• Cilia biology

Background:

• Signaling receptors, including G protein-coupled receptors (GPCRs), are known to exit cilia upon activation.
• The BBSome complex mediates the retrieval of activated receptors from cilia back into the cell.

Purpose of the Study:

• To investigate the mechanism of activated GPCR release from cilia when BBSome-mediated retrieval fails.
• To identify the cellular machinery involved in this release process.
• To understand the physiological and pathological implications of this alternative clearance pathway.

Main Methods:

• Observation of GPCR behavior at ciliary tips using advanced microscopy.
• Analysis of the roles of actin and associated proteins (drebrin, myosin 6) in receptor release.
• Genetic manipulation of BBSome function and receptor retrieval determinants.
• Assessment of Hedgehog signaling pathway activity in wild-type and mutant contexts.

Main Results:

• Activated GPCRs that evade BBSome retrieval accumulate in ciliary tip buds and are released as ectosomes.
• Actin, drebrin, and myosin 6 are essential for the ectosome release process (ectocytosis).
• Signal-dependent ectocytosis selectively removes activated signaling molecules from cilia.
• Ectocytosis compensates for BBSome defects, enabling Hedgehog signal transduction in Bbs mutants.
• Ciliary receptors lacking retrieval signals undergo ectocytosis even in wild-type cells.

Conclusions:

• Signal-dependent ectocytosis is a novel, selective mechanism for removing activated signaling receptors from cilia.
• This process plays a role in regulating ciliary signaling in both normal physiology and disease states.
• Ectocytosis provides a compensatory pathway for ciliary receptor clearance when canonical retrieval mechanisms are impaired.