Researchers have proposed and validated a novel mechanism that addresses a decades-old mystery surrounding the sorting and delivery of specialized proteins in epithelial cells. This breakthrough sheds light on a fundamental process in cell biology and could have important implications for understanding and treating diseases such as cancer.
The apical protein sorting puzzle
Epithelial cells are faced with the harsh environment being at the interface between us and the outside world, they are specialized in that respect. They are what line our body surfaces such as the skin, gut lining, or airways. Maintaining such polarity is possible because the cells have top (also called apical) and side (also called lateral) surfaces, each of which depends on different proteins to work properly.
Scientists have been baffled for decades over how epithelial cells sort and transport these special proteins to their correct addresses, most notably the apical surface. Although the mechanism for delivering proteins to the lateral surface is well characterized, that responsible for apical sorting remains poorly understood due to an apparent absence of ‘zip codes’ in a sizable population of molecules.
For the first time, a group of researchers headed by University of Cambridge Ph. Student in the laboratory of Ian Macara at Vanderbilt University, presents and validates a new hypothesis that might finally solve this mystery.
The Size Matters Principle
Published in the prestigious journal Nature Cell Biology, de Caestecker’s research indicates that the size of the cytoplasmic domain – the part of the protein that sits inside the cell — is a key factor in determining whether or not a protein if targeted to either apical or lateral surface.
The outlook of proteins aimed for the apical membrane and many have shorter cytoplasmic tails, and those bound for the lateral surface often contain longer cytoplasmic domains [9]. Based on this finding, de Caestecker speculated that the Golgi — an essential organelle within the cell’s protein-processing and sorting apparatus — may employ a “size filter” to specify where each protein needs to go.
To test this notion, the team took cell culture and used synthetic biology to shorten the cytoplasmic tails of these three type-morphant apical proteins. When they elongated the tails, they discovered that the proteins were processed and exited from the Golgi delayed significantly and instead of being delivered to the apical membrane, were misdelivered to the lateral surface. This indicates that the length of the cytoplasmic tail is an important factor in Golgi-targeting decisions.
Conclusion
According to the Vanderbilt University team, their research unveils a mystery decades in the making within the field of epithelial cell biology. In proposing and validating the ‘size filter’ mechanism at the Golgi, researchers have opened a new chapter in the story of how epithelial cells appropriately sort and deliver their specialized proteins to correct cell surfaces.
The findings not only contribute to a more complete understanding of the basic principles governing how cells work but also could help scientists understand diseases such as cancer that result when polarized protein sorting goes awry. With an understanding of how these processes work, scientists can now start to devise improved diagnostic modalities and precision-based interventions for many diseases characterized by dysfunction in epithelial cells. We are on our way to the future of even better upcoming discoveries in this fascinating research field.
