Collaborative Research: Mechanics of Tension-Induced Adaptation in Clathrin-Mediated Endocytosis

University Of Houston, Houston TX

Investigators

Abstract

Transport of macromolecules into cells occurs via a collection of pathways, commonly referred to as endocytosis. These pathways are characterized by a chain of remodeling events during which an almost flat patch of plasma membrane is transformed into a cargo-carrying closed vesicle. The most commonly used pathway is called clathrin-mediated endocytosis (CME) which is important for the exchange of lipids and proteins between the plasma membrane and organelles. As such, CME is critical for maintaining the organization of the plasma membrane and regulating various cellular processes. Recent research on CME suggests that cells sense the mechanical environment by adapting the protein machinery to ensure successful CME. How cells sense and adapt to the mechanical environment to maintain cellular transport is not well understood. The goal of this project is to gain mechanistic insights into this dynamic adaptation in cells via combined theoretical and experimental approaches. Since cells experience varied mechanical environments in different diseased states, this work can provide fundamental insights into cellular transport in diseased cells that can help facilitate the design of improved nanoparticle-based drugs. This work will offer a physical explanation for the observed "mechanosensitivity" and tension-based adaptation in clathrin-mediated endocytosis. To achieve this objective, continuum mechanics and Monte Carlo simulations of membrane-protein interactions will be complimented with high-resolution live cell and super-resolution fluorescence microscopy to test the competing explanations for assembly of membrane-associated proteins and tension-induced adaptation in CME. This study will address two major debates in the endocytosis literature. First, it will identify the energetically optimal mechanism by which clathrin drives membrane curvature. Second, it will identify the mechanism by which membrane senses tension and recruits actin filaments for driving vesicle growth. The numerical and experimental findings will quantify the extent to which the key membrane-remodeling proteins can counter tension and drive vesicle growth. Overall, these findings would reveal the general principles by which tension regulates the assembly of membrane-remodeling proteins.