Clathrin is a self-assembling protein that controls the formation of intracellular transport vesicles required for several key membrane traffic pathways. These include receptor-mediated endocytosis and biogenesis of lysosomes and secretory granules. Thus clathrin plays a critical role in cell growth control, antigen presentation, neuronal function and hormone secretion. Malfunction of clathrin pathways is associated with development of cancer, heart disease and neuronal defects. Clathrin-mediated pathways are also subverted by certain viruses and intracellular bacteria to facilitate their infection. A novel isoform of clathrin (CHC22) that is primarily expressed in skeletal muscle, cardiac muscle and fat has been recently characterized by the Brodsky laboratory. Its tissue-specific function is to package the GLUT4 glucose transporter into intracellular vesicles that are released in response to insulin stimulation, leading to clearance of glucose from the bloodstream. This CHC22 clathrin isoform is therefore associated with pathways that are defective in type 2 diabetes. The focus of the Brodsky laboratory since 1982 has been to define the biochemistry, regulation, evolution and physiological function of the clathrin subunits and their isoforms, focusing on their role in disease states, as well as in normal cellular physiology. The laboratory has made significant contributions in these areas over the years and maintains an international reputation for expertise on clathrin structure and function.
There are four current projects in the laboratory. These projects aim to define the comparative functions of the two clathrin heavy chain (CHC) isoforms (CHC17 and CHC22) and the two clathrin light chain isoforms (LCa and LCb). The regulation of CHC17 clathrin function by signaling pathways and the cooperation of CHC17 clathrin with the actin cytoskeleton through clathrin light chain interaction with the actin-binding Hip proteins is being investigated in the context of cell adhesion and migration. Establishing the mechanistic role of CHC22 clathrin in GLUT4 transport and pathways that malfunction in type 2 diabetes is also a major goal for the laboratory.