Endocytosis is one of the main routes of cargo transport into cells across the cell membrane. It is used by cells to communicate with each other, internalize nutrients, and sense environmental cues, and it can be hijacked by pathogens. One of the most essential cellular pathways of cargo uptake is clathrin-mediated endocytosis. It is indispensable for cellular homeostasis, although other internalization routes exist. Thus, researchers have been fascinated with clathrin-mediated endocytosis for more than half a century.
The cover image for the February 21 issue of Biophysical Journal is a temporal color code of clathrin dynamics at the basal plasma membrane of a Cos-7 cell. The images were captured with simultaneous two-wavelength axial ratiometry (STAR) microscopy, a powerful total internal reflection fluorescence-based technique allowing researchers to resolve the nanometer axial distribution of fluorescently tagged proteins. The cover is a projection of a 5-minute-long movie onto a single image, where each frame is color coded for time. The clathrin accumulations that are present at the beginning of the imaging sequence are color coded blue, and clathrin structures appearing in the middle and at the end are color coded yellow and red, respectively. Clathrin structures present throughout the imaging appear white.
This image from our research highlights how dynamically clathrin associates with the plasma membrane. Interestingly not all the dynamic clathrin sites lead to internalization, a key detail that can be elucidated with STAR. As a scientific community, we have just begun to appreciate the heterogeneity of clathrin fates, and the role of flat versus curved clathrin accumulation in living cells and tissues is yet to be defined.
Why would 50 years of research on these details matter? One reason is that life is dependent on clathrin-mediated endocytosis. It allows tissues to differentiate during development, facilitates synaptic transmission, and governs fight-or-flight responses. Hence, the answer is simple: parsing out those dynamics brings us closer to harnessing clathrin-mediated endocytosis to advance human health. Modulating its tempo or selectively inhibiting it without disrupting cell homeostasis could have a profound impact on efficient tissue-specific drug delivery or prevention of virus internalization. High-resolution dynamic imaging approaches will be instrumental in untangling the regulation of clathrin-mediated endocytosis by the ever-changing cellular and biophysical context in which it appears.
— Tomasz J. Nawara, William F. Dean, and Alexa L. Mattheyses