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Published on: December 23, 2015
Myoferlin is critical for endocytosis in endothelial cells
Pascal N Bernatchez1, Arpeeta Sharma, Pinar Kodaman
1The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Abstract:
Myoferlin is a member of the ferlin family of proteins that promotes endomembrane fusion with the plasma membrane in muscle cells and endothelial cells. In addition, myoferlin is necessary for the surface expression of vascular endothelial growth factor receptor 2 through the formation of a protein complex with dynamin-2 (Dyn-2). Since Dyn-2 is necessary for the fission of endocytic vesicles from the plasma membrane, we tested the hypothesis that myoferlin may regulates aspects of receptor-dependent endocytosis. Here we show that myoferlin gene silencing decreases both clathrin and caveolae/raft-dependent endocytosis, whereas ectopic myoferlin expression in COS-7 cells increases endocytosis by up to 125%. Interestingly, we have observed that inhibition of Dyn-2 activity or caveolin-1 (Cav-1) expression impairs endocytosis as well as membrane resealing after injury, indicating that Dyn-2 and Cav-1 also participate in both membrane fission and fusion processes. Mechanistically, myoferlin partially colocalizes with Dyn-2 and Cav-1 and forms a protein complex with Cav-1 solubilized from tissue extracts. Together, these data describe a new role for myoferlin in receptor-dependent endocytosis and an overlapping role for myoferlin-Dyn-2-Cav-1 protein complexes in membrane fusion and fission events.
Insights
Myoferlin regulates endocytosis by interacting with dynamin-2 and caveolin-1, impacting both membrane fusion and fission processes. This discovery reveals a novel role for myoferlin in cellular membrane dynamics.
Area of Science:
- Cell Biology
- Molecular Biology
- Membrane Trafficking
Background:
- Myoferlin, a ferlin family protein, is crucial for endomembrane fusion in muscle and endothelial cells.
- It is essential for surface expression of vascular endothelial growth factor receptor 2 via complex formation with dynamin-2 (Dyn-2).
- Dyn-2 is known to be necessary for the fission of endocytic vesicles from the plasma membrane.
Purpose of the Study:
- To investigate the role of myoferlin in receptor-dependent endocytosis.
- To determine if myoferlin influences clathrin and caveolae/raft-dependent endocytic pathways.
- To explore the functional relationship between myoferlin, Dyn-2, and caveolin-1 (Cav-1) in membrane dynamics.
Main Methods:
- Myoferlin gene silencing and ectopic expression in COS-7 cells.
- Assays to measure clathrin and caveolae/raft-dependent endocytosis.
- Inhibition of Dyn-2 activity and Cav-1 expression.
- Analysis of protein colocalization and complex formation.
Main Results:
- Myoferlin gene silencing reduced both clathrin and caveolae/raft-dependent endocytosis.
- Ectopic myoferlin expression increased endocytosis by up to 125%.
- Inhibition of Dyn-2 or Cav-1 impaired endocytosis and membrane resealing, suggesting their roles in both fission and fusion.
- Myoferlin partially colocalized and formed a complex with Cav-1.
Conclusions:
- Myoferlin plays a significant role in regulating receptor-dependent endocytosis.
- Myoferlin, Dyn-2, and Cav-1 participate in both membrane fusion and fission events.
- These findings reveal a novel function for myoferlin in cellular membrane trafficking and dynamics.
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