Membrane trafficking: Polar express

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The vesicular coat protein clathrin is not only essential for endocytosis and cell signaling processes at the plasma membrane, it also has a role in intracellular trafficking and the maintenance of epithelial polarity.

The vesicular coat protein clathrin is essential for endocytosis and cellular signalling processes at the plasma membrane. A new study in Nature uncovers an additional role for clathrin in intracellular trafficking and the maintenance of epithelial polarity.

The establishment of epithelial cell polarity is essential for the correct physiological function of many tissues and requires the polarized distribution of plasma membrane proteins into apical and basolateral domains. To test whether clathrin might be involved in epithelial polarity, Rodriguez-Boulan and co-workers used small interfering RNAs (siRNAs) to knock down clathrin expression in epithelial cells and looked at the distribution of basolateral and apical markers by confocal microscopy. Interestingly, the distribution of numerous basolateral membrane proteins was disrupted, whereas the localization of apical proteins was not affected by the treatment.

It is possible that the depletion of clathrin affects basolateral polarity by preventing the formation of functional tight junctions, which keep the apical and basolateral membrane domains of polarized cells separated. However, the morphology and function of tight junctions in clathrin-depleted cells were normal.

So, what alternative explanation could there be? Using biochemical targeting assays, the authors showed that clathrin knockdown selectively delayed the delivery of basolateral proteins to the plasma membrane and caused their mis-sorting to the apical surface in both biosynthetic and recycling routes, whereas it had no effect on the delivery of apical proteins. Furthermore, the authors introduced green fluorescent protein (GFP)-tagged basolateral or apical plasma proteins into clathrin-depleted cells and imaged their exit from the trans-Golgi network (TGN) at high resolution in live cells. They found that knockdown of clathrin expression reduced the TGN exit kinetics of only basolateral membrane proteins and caused the mis-sorting of basolateral proteins into apical carrier vesicles. This explains their reduced delivery to the basolateral surface and their increased delivery to the apical surface.

Taken together, this work provides evidence that clathrin-coated vesicles are essential for sorting basolateral plasma membrane proteins from the Golgi complex and recycling endosomes to the basolateral membrane domain of polarized epithelial cells. Given that epithelial polarity is lost in many tumours, it will be interesting to study whether this function of clathrin might be disrupted in some types of cancer and whether clathrin could become a therapeutic target for these cancers.

Francesca Cesari

References

Deborde, S. et al. Clathrin is a key regulator of basolateral polarity. Nature 452, 719–723 (2008) | Article | PubMed |
Edeling, M. A., Smith, C. & Owen, D. Life of a clathrin coat: insights from clathrin and AP structures. Nature Rev. Mol. Cell Biol. 7, 32–44 (2006) | Article | PubMed |
Rodriguez-Boulan, E., Kreitzer, G. & Müsch, A. Organization of vesicular trafficking in epithelia. Nature Rev. Mol. Cell Biol. 6, 233–247 (2005) | Article | PubMed |