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Special delivery: new functions for an old friend for fast-tracking membrane components necessary to build the cell's antennae

In a study recently published in eLife, Dr Pleasantine Mill and colleagues discover that protein complex IFT plays essential roles in delivering cargos to the base of the cilia and in facilitating their entry: November 2021

While we understand more about how and when information contained within our DNA is translated into proteins, how these new components find their way to the correct ‘address’ in a cell is less clear. Cargos are often produced a significant distance from where they are needed to function, which is certainly the case for cilia.

Cilia have a unique lipid and protein composition from the rest of the cell and act as antennae, allowing cells to sense key developmental and environmental signals. No protein synthesis occurs within cilia - every component must be transported to, and selectively imported, inside. Once within the cilia, a motor-driven multi-protein traffic module called intraflagellar transport (IFT) drives cargo from the base to the tip of the cilia and back to dynamically regulate its contents.

IFT is essential for cilia assembly and maintenance across organisms. Mutations which disrupt a component of the IFT machinery, WDR35, in humans and mice result in severe congenital anomalies (Mill et al, 2011).

Current models suggest IFT picks up cargos at the cilia base but how the cell efficiently delivers these diverse cargos from their site of synthesis to where they are needed has not been fully understood until now.

In cells from patients and mice, cilia form at normal numbers but appeared stalled at a rudimentary size and failed to enrich in membrane cargos. Understanding how new components find their way to the correct subcellular ‘address’ would shed light on how cells assemble functional organelles.

This study shows that WDR35 and core IFT-A proteins display deep sequence and structural homology to the classic protein coat complex COPI.  The research team demonstrated that purified IFT-A can directly bind to specific types of lipids.

Electron microscopy revealed that at the base of cilia of control cells there are few vesicles, some of which have electron density around them. In contrast, small vesicles, lacking this electron dense coat, pile-up around the rudimentary Wdr35-/- cilia.

Further to this, the team also showed that WDR35 localized to these vesicles in controls.

This study provides the first in-situ evidence that WDR35, likely with other IFT-A proteins, acts as a novel coat complex necessary for delivery of membrane cargo to allow cilia elongation and function as a signalling organelle.

Better understanding of how a cell targets cargos to cilia - a process shown to be dependent on WDR35 -  opens up new questions about additional contributors as well as the nature of the vesicles shown to be accumulating.

Further studies are needed to explore what they are carrying and where they come from, however this work provides a crucial starting point to begin looking at how different ciliopathy patient mutations affect different steps in traffic to and within cilia, helping us better understand the phenotypic spectrum seen in clinic.

 

In this work, we find that a protein complex called IFT, known to play key roles in moving cargos within the cilia, also plays essential roles in delivering cargos to the base and allowing entry into cilia. Without this IFT-A complex, as seen in cells from patients or mouse models of ciliopathies, vesicles with cargo pile up around cilia but cannot enter to allow cilia to grow and function properly. For many years, we and others in the field had postulated a ‘coat protein’ function for IFT-A - here we provide the first in situ evidence to demonstrate this! We have been able to visualize precisely where these proteins are acting in the cell outside of cilia and how traffic to developing cilia goes very wrong without this complex.

Dr Pleasantine MillMRC Human Genetics Unit
cilia schematic