Protein Trafficking to the Primary Cilium: Molecular Pathways and Clinical Implications

The primary cilium is a critical cellular organelle involved in various signaling pathways essential for cellular communication and function. Protein trafficking to the primary cilium is a highly regulated process, ensuring the correct localization and function of ciliary proteins necessary for development and homeostasis. Disruptions in these trafficking pathways can lead to a range of ciliopathies, a group of genetic disorders characterized by defects in the structure or function of cilia, resulting in conditions such as polycystic kidney disease, retinal degeneration, and Bardet-Biedl syndrome. Understanding the molecular mechanisms underlying protein trafficking to the primary cilium is vital for elucidating the pathogenesis of these diseases and developing targeted therapeutic interventions. This research area bridges fundamental cell biology and clinical applications, highlighting the significance of precise intracellular transport processes in health and disease.

The ciliary membrane has a distinct protein and lipid composition compared to the rest of the plasma membrane. While cilia-localized proteins are not exclusive to the ciliary membrane, the small size of the cilium facilitates the enrichment of these proteins, enabling effective reception and amplification of chemical or mechanical signals. This compartmentalization also generates transcriptional effectors and modifies transcriptional outputs, fundamentally impacting downstream pathways driving morphogenesis. The uniqueness of the ciliary membrane is maintained by a barrier structure called the ciliary gate at the base of the cilium, which regulates protein entry and exit. Although small proteins like tubulin may enter cilia by diffusion, many proteins are restricted and require additional factors for proper localization. Intra-flagellar transport (IFT) complexes are central to ciliary trafficking, and recent high-resolution structures of IFT-A complexes have provided detailed insights into this process. However, the involvement of additional factors and a comprehensive understanding of the detailed mechanisms remain to be elucidated. Furthermore, the targeting of proteins from their production sites within the cell to the base of the cilium is not yet clearly understood.

In this special topic we focus on multiple aspects in relation to ciliary protein trafficking such as sorting of cargoes for cilia, transporting cargoes into cilia, cargo retrieval from cilia, retention of cargoes inside cilia, restriction of cargoes from reaching cilia, recycling in the endosomal compartment and loss of proteins through release of ciliary membrane vesicles. Key questions in studying protein trafficking to the primary cilium include identifying specific molecular pathways and mechanisms, understanding motor protein and IFT complex functions, determining signals for cargo selection and sorting, and exploring how trafficking is regulated during the cell cycle and by post-translational modifications. In addition, recent structural insights and technological advances in imaging, proteomics, and genomics are essential for a deeper understanding of these processes. Further, it is crucial to understand how defects in these pathways cause ciliopathies and identify therapeutic targets.

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Technology and Code

Keywords: Primary cilium, protein trafficking, ciliopathies, ciliary cargo, ciliary signaling

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