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A non-canonical role for dynamin-1 in regulating early stages of clathrin-mediated endocytosis in non-neuronal cells

Saipraveen Srinivasan, Christoph J. Burckhardt, Madhura Bhave, Zhiming Chen, Ping-Hung Chen, Xinxin Wang, Gaudenz Danuser, Sandra L. Schmid

Preprint posted on January 22, 2018 https://www.biorxiv.org/content/early/2018/01/22/251983?%3Fcollection=

The roles of dynamin-1 in neurons are well studied, but what is its function in non-neuronal cells? This preprint investigates the roles of dynamin in regulating early stages of clathrin-mediated endocytosis.

Selected by Penelope La-Borde

Background

The title of this preprint caught my attention, as I am interested in clathrin-mediated endocytosis (CME). In addition to the well-studied roles of dynamin-1 (Dyn1) in membrane fission during the rapid recycling of synaptic vesicles in neurons, dynamin also plays a role in regulating early stages of CME. Little is understood about this regulatory role and the work in this preprint seeks to investigate further.

Key findings

This preprint studies the isoform-specific roles of Dyn1 and dynamin-2 (Dyn2) in regulating early stages of CME, revealing that they have distinct functions. Dyn1 and Dyn2 are shown to be differently recruited to clathrin-coated pits (CCPs). Dyn2 is gradually recruited to CCPs and displays a burst of accumulation when the clathrin-coated vesicle (CCV) is released, whereas Dyn1 recruitment to CCPs is barely detectable. Despite these low levels of Dyn1, the researchers found that activation of Dyn1 increases rates of CCP initiation and maturation. They also identified Sorting nexin 9 (SNX9) as a binding partner of active Dyn1, required for its effect on CCP maturation.

Why is this preprint important?

To show the physiological relevance of their findings, the researchers studied the effect of epidermal growth factor (EGF) on Dyn1. They found that Dyn1 is activated downstream of epidermal growth factor receptors (EGFRs), increasing CCP initiation and maturation rates.

What I like about this preprint

I like the use of genome-edited cells in this work, enabling the authors to study the dynamin isoforms at their endogenous levels. This avoids many of the potential problems involved with overexpression of the protein of interest. This is a very thorough study, using multiple approaches to confirm key findings.

Future directions

Next steps for this work could include identifying more isoform-specific binding partners for dynamin in non-neuronal cells. Whilst SNX9 has been revealed as a binding partner for active Dyn1 that is required for its CCP maturation effects, it would be interesting to discover any binding partners that mediate the effects of Dyn1 on CCP initiation. The functions of SNX9 in CME could be elucidated further; perhaps, even its Dyn-1 binding site could be discovered, allowing mutagenesis of this site for further study.

Another area for future work suggested in the preprint is to investigate whether other signalling receptors can modify the composition of their CCPs to change their maturation rates, possibly involving Dyn1, as it is the case for EGFRs.

Furthermore, to investigate how Dyn1 and Dyn2 achieve their distinct functions in regulating early stages of CME, it would be interesting to discover which specific residues are responsible for these functions. This would then allow mutagenesis studies, potentially switching the functionalities between the isoforms by mutating key residues.

It could also be interesting to study dynamin-3, the third isoform of dynamin in vertebrates, to see whether it has distinct functions to Dyn1 and Dyn2.

 

Posted on: 29th April 2018

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