ERM proteins: The missing actin linkers in clathrin-mediated endocytosis
Preprint posted on April 25, 2018 https://www.biorxiv.org/content/early/2018/04/25/307272
It has long been known that actin recruitment is required at sites of clathrin-mediated endocytosis (CME) to help promote vesicle formation and dynamin-dependent scission from the plasma membrane. The way in which actin is recruited to the clathrin-coated pits has, however, remained elusive. For the first time, this study demonstrates that actin-binding ERM family proteins are recruited to clathrin-coated pits in the very early stages of their formation. As ERM proteins are capable of simultaneously binding both actin and cell surface receptors internalised by CME, these proteins could provide the missing physical link between actin and the clathrin machinery.
I chose this paper to PreLight as the discovery of a new component of the clathrin coat machinery is quite remarkable considering how long and extensively these structures have been studied, especially one that fills a long-standing hole in our model of events at these sites.
The clathrin adapter AP2 is a multi-subunit protein complex found on the cytoplasmic side of the plasma membrane where it binds to both clathrin and transmembrane receptors to coordinate CME. In this study the authors use a GFP-tagged version of AP2 and a combination of TIRF microscopy and biochemistry to monitor interactions and events occurring in clathrin coated pits at the cell surface. The key findings are:
- ERM proteins co-precipitate and colocalise with the clathrin adapter AP2
- Inhibition of ERM protein function with both an inhibitor and by RNAi negatively impacts the rate of clathrin pit formation and increases the number of arrested AP2 positive structures in a comparable manner to actin inhibition
- The ERM protein ezrin is recruited to clathrin coated pits at the very early stages of their formation, coinciding with the first burst of actin recruitment.
Given the ability of ERM proteins to simultaneously bind actin and transmembrane receptors (with their C-terminal and FERM domains respectively) the authors conclude that ERM proteins are very likely the missing factors responsible for recruiting actin to clathrin coated pits and are required for efficient CME.
- Is receptor binding required to recruit the ERM proteins to the clathrin coated pits?
- Do ERM proteins help to cluster receptors prior to CME?
- Are ERM proteins recruited to all clathrin coated pits, or are they required for a certain subset of events involving particular cargo?
- It will also be important to consider how ERM protein function at the cell cortex may affect clathrin-mediated endocytosis.
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