Possible regulation of caveolar endocytosis and flattening by phosphorylation of F-BAR domain protein PACSIN2/Syndapin II

Abstract

Caveolae are flask-shaped invaginations of the plasma membrane. The BAR domain proteins form crescent-shaped dimers, and their oligomeric filaments are considered to form spirals at the necks of invaginations, such as clathrin-coated pits and caveolae. PACSIN2/Syndapin II is one of the BAR domain-containing proteins, and is localized at the necks of caveolae. PACSIN2 is thought to function in the scission and stabilization of caveolae, through binding to dynamin-2 and EHD2, respectively. These two functions are considered to be switched by PACSIN2 phosphorylation by protein kinase C (PKC) upon hypotonic stress and sheer stress. The phosphorylation decreases the membrane binding affinity of PACSIN2, leading to its removal from caveolae. The removal of the putative oligomeric spiral of PACSIN2 from caveolar membrane invaginations could lead to the deformation of caveolae. Indeed, PACSIN2 removal from caveolae is accompanied by the recruitment of dynamin-2, suggesting that the removal provides space for the function of dynamin-2. Otherwise, the removal of PACSIN2 decreases the stability of caveolae, which could result in the flattening of caveolae. In contrast, an increase in the amount of EHD2 restored caveolar stability. Therefore, PACSIN2 at caveolae stabilizes caveolae, but its removal by phosphorylation could induce both caveolar endocytosis and flattening.

Keywords: BAR domain; caveolae; mechanical stress; phosphorylation; protein kinase C.

Figure 1.

Domain structure of PACSIN2/Syndapin II and its binding proteins. (A) The domains of PACSIN2 and their binding proteins are illustrated. (B) The putative oligomeric spiral of PACSIN2 F-BAR domain around the membrane tubules. The F-BAR domain is supposed to form filamentous spiral, which assembles on the surface of membrane tubules such as those observed in the plasma membrane invaginations such as caveolae.

Figure 2.

A model of caveolar endocytosis mediated by PACSIN2 phosphorylation through PKC activation by mechanical stress. PACSIN2 oligomerizes and binds to the necks of caveolae. PACSIN2 is phosphorylated by PKC upon mechanical stimuli, such as hypotonic stress and shear stress, and phosphorylated PACSIN2 dissociates from the necks of caveolae. This enables dynamin-2 to occupy the space after the removal of PACSIN2, which induces caveolar scission and endocytosis. Otherwise, the loss of PACSIN2 at the caveolar neck leads to caveolar flattening, to buffer membrane tension.