AI-based network analysis of single molecule super resolution microscopy: New insights into the caveolin-1 response to membrane tension

 

Caveolae are plasma membrane invaginations formed by interaction of the membrane protein caveolin-1 with the adaptor protein cavin-1. They have long been thought to be an endocytic portal and also attributed roles in cell signaling, via the highly conserved caveolin scaffolding domain (CSD). However, caveolae are actually stable at the plasma membrane where they function as a membrane buffer, flattening in response to mechanical stress and protecting cells from membrane rupture and death. AI based network analysis (SuperResNET) of single molecule localization microscopy has allowed us to determine the structure of caveolae and non-caveolar caveolin-1 oligomers, or scaffolds, in the plasma membrane. Both caveolae and scaffolds interact with cavin-1 that impacts their shape and organization. Scaffolds released upon caveolae flattening regulate receptor signaling via the CSD and, upon reduced membrane tension, are internalized via CLIC endocytosis to lysosomal vacuoles or reservoirs from which they can recycle to the cell surface. Caveolae flattening and CLIC endocytosis to lysosomal reservoirs define dual and complementary mechanisms by which caveolin-1 contributes to the cell’s mechanical response to changes in membrane tension.