The BAR domain-mediated membrane remodeling for the cellular morphogenesis and vesicle generation

 

Shiro Suetsugu

Nara Institute of Science and Technology

 

The shaping of the cellular membrane is essential for cellular functions through the morphogenesis of various subcellular structures. The morphology of membrane, i.e., membrane curvatures, is generated by the Bin-Amphiphysin-Rvs (BAR) family proteins. We have been identified various BAR domain-containing proteins for various subcellular structure formation, including membrane invagination including clathrin-coated pits, caveolae, and phagocytotic cup, as well as membrane protrusions including filopodia. The membrane invaginations are cut into vesicles for intracellular trafficking. However, the cutting of filopodia had not been described. The vesicles at the outside of the cells are known as extracellular vesicles (EVs). EVs are classified as large EVs (l-EVs, or microvesicles) and small EVs (s-EVs, or exosomes). S-EVs are thought to be mainly generated from endosomes through a process that mainly depends on the ESCRT protein complex. However, the mechanisms of l-EV generation from the plasma membrane have not been identified. Among BAR domains, the inverse BAR (I-BAR) proteins are involved in filopodial protrusions. Recently, we showed that the I-BAR proteins generate l-EVs by scission of filopodia. Interestingly, I-BAR-dependent l-EV production was promoted by in vivo equivalent external forces. Especially, one of the I-BAR proteins, missing in metastasis (MIM) -dependent l-EV production was also promoted by the suppression of ALIX, a ESCRT component, suggesting an alternative mechanism of vesicle formation to s-EVs. The MIM-dependent l-EVs had the enrichment of the proteins, including IRS4 and Rac1, which stimulated the migration of recipient cells through lamellipodia formation. The l-EVs had abundant lysophospholipids, which promoted the l-EV generation. Thus, these filopodia-dependent l-EVs, which we named filopodia-derived vesicles (FDVs), modify cellular behavior.

 

1) Developmental Cell 2021;56 (6), 842-859

2) Trends Cell Biol. 2021; 31(8):644-655

3) J Biol Chem. 2006;281(46):35347-58