Clathrin plaques form mechanotransducing platforms
Preprint posted on May 14, 2018 https://www.biorxiv.org/content/early/2018/05/14/321885?%3Fcollection=
Clathrin plaques are the new focal adhesions: Adhesive clathrin plaque association with the cytoskeleton provides a novel platform for mechanosensing, including the regulation of YAP/TAZ signaling.Amanda Haage
Why This Is Cool – The authors provide evidence that two relatively new discoveries in cell biology, mechanotransduction via YAP/TAZ signaling and large clathrin plaque structures on the plasma membrane, work together to produce a novel platform for sensing mechanical input, connecting and regulating the cytoskeleton, and integrating various signaling pathways. These are the roles that have previously been established for focal adhesions. It makes sense that cells could complete these essential tasks in a variety of ways using other large membrane-associated protein complexes. The authors provide exhaustive evidence for the mechanisms and relevance of this new system. First, they demonstrate using beautiful images of immunogold labeling with metal-replica EM (Fig1) the precise organization of the clathrin plaques surrounded by branched actin and desmin intermediate filaments on primary mouse myotubes. Next they show that these structures respond to mechanical stimuli by subjecting the myotubes to cyclic stretching. Upon stretching the plaques decrease in size supposedly due to an increase in endocytosis and the YAP/TAZ mechanotransducers canonically accumulate in the nucleus with a concurrent increase in their target genes’ expression levels. Interestingly, myotubes without clathrin plaques had high levels of YAP/TAZ nuclear staining without stretching with no obvious response to stretch. The authors go on to demonstrate this is because the clathrin plaques act as sticky nets that sequester YAP/TAZ until the cell receives a mechanical input. They propose that YAP/TAZ gets stuck at the actin network surrounding clathrin plaques largely through an interaction between TAZ and Dynamin 2. Myotubes without Dynamin 2 lose their actin organization, and their ability to translocate YAP/TAZ in response to stretch. Now that they have established a mechanism for how clathrin plaques can act as mechanosensors, the authors go on to show the relevance of this mechanism in vivo. A type of centronuclear myopathy is caused by mutations in Dynamin 2. By using a knock-in mouse model for the most common human mutation linked to this disease, they demonstrate similar phenotypes to the Dynamin 2 knockout myotubes. These mice were found to have disorganized clathrin plaques, TAZ, and desmin in their muscles. In addition, primary culture of their mytotubes revealed a decrease in TAZ nuclear localization without mechanical input. To really drive the point home, the authors also repeat these findings in immortalized myotubes from a centronuclear myopathy human patient.
Why I Selected It – The idea that cells can sense and respond to the physical properties of their microenvironment has always fascinated me. It’s a newer concept that has burst into a huge field of cell biology. We are now getting beyond the initial discoveries of this phenomenon and learning just how much it permeates every part of cell biology. Mechanotransduction is not just a field for cell migration or extracellular matrix people, but is a field for everyone.
Open Questions –
- Has YAP/TAZ translocation via endocytosis been directly observed? Is it something that could be observed via live imaging?
- Do the clathrin plaques ever recover in size and YAP/TAZ content after extended periods of relaxation?
- Could the Dynamin 2 – TAZ interaction be a realistic drug target for centronuclear myopathy?
Related References –
- What is YAP/TAZ?
- Dupont S. Role of YAP/TAZ in cell-matrix adhesion-mediates signaling and mechanotransduction. Exp Cell Res. (2016) 10;343(1):42-53/
- What are clathrin plaques?
- Lampe M., Vassilopoulos S., Merrifield C. Clathrin coated pits, plaques and adhesion. J Struct Biol. (2016) 196(1):48-56.
- Mutations in Dynamin 2 cause centronuclear myopathy
- Bitoun M., Maugenre S., Jeannet PY., Lacene E., Ferrer X., Laforet P., Martin JJ., Laporte J., Lochmuller H., Beggs AH., Fardeau M., Eymard B., Romero NB., Guicheney P. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. (2005) 37(11):1207-9.
Posted on: 6th June 2018Read preprint
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