In the journal Cell, researchers publish a deep analysis of the HPA primary cilia section, first introduced in HPA v24. The HPA subcellular resource portrays primary cilia as the most heterogeneous organelles, customized by the cell for fine-tuned environmental sensing, and inspires many new views on this tiny antenna.

The primary cilium is a tiny antenna-like structure that is built by almost any human cell to sense the local environment. It is 5000 times smaller compared to the cell. Primary cilia are distinct from their better-known siblings "motile cilia", which move mucus out of the lungs or propel cells like the sperm cell. The primary cilium is tailored to sensory roles, equipped with receptors to sense "environmental cues" like hormones. From hereditary diseases with dysfunctional cilia ("ciliopathies") we know that cilia contribute to development and function of most body tissues. Yet, since these organelles are so difficult to study due to their size, little is known about their functioning and protein makeup.

In a tour de force, continuously running a microscopy-based analysis pipeline over three years, HPA researchers pictured more than 128,000 individual cilia, identifying and localizing 715 ciliary proteins to ciliary sub-regions across three different cell types. Surprisingly, 69% of the 715 proteins were detected only in the primary cilium in cells of one or two of the three cell types. Even within the same cell type only 22% of the proteins could be found in all cilia. "We observed that primary cilia are highly adaptable and versatile sensors for the cell. Cells seem to customize the protein composition of their cilia to have them perform specific sensing tasks." says Emma Lundberg, director of the HPA subcellular resource.

The researchers discovered 91 proteins that had never been linked to primary cilia before. Jan Hansen, postdoctoral researcher at HPA and the first author of the study, explains: "These new ciliary proteins inspire many new hypotheses about cilia. For example, we identified components of many signal transduction pathways, highlighting that cilia not only receive signals but also process and combine the information for the cell." Also functionally, the new proteins provide new perspectives on cilia. For example, some of them are known as neuronal or synapse proteins, highlighting the implications of cilia in brain functions and their capability to form sensory contacts to neighboring cells.

Collaborating with clinicians from Karolinska Institutet, the HPA researchers explored the clinical relevance of their findings through analyzing genetic data from patients with undiagnosed syndromes. Thereby, they found a promising candidate gene, CREB3, in a child with symptoms resembling ciliopathies. Ciliopathies present with very diverse phenotypes, such as skeletal changes, mental deficits, blindness, or kidney defects. Understanding the role of cilia in different human cell types has been limited because of the difficulty in studying their protein composition. This made it hard to discover rare genetic variants as potential ciliopathies. The spatial atlas of cilia proteins in the HPA can contribute towards a better understanding and diagnosis of rare ciliopathy disorders.

Read the article: https://doi.org/10.1016/j.cell.2025.08.039