IN HEALTH, AGING, AND DISEASE

Understanding how cells organize, shape, and move their membrane-bound organelles is one of the most fundamental problems in biology.  To address this challenge, our work focuses on: (1) determining how the actin and microtubule cytoskeletons normally control membrane dynamics, and (2) deciphering how cytoskeleton-driven membrane remodeling is altered in the pathogenesis of infectious diseases, genetic disorders, and aging.

The overarching goal of all the projects in the lab is to understand the mechanisms by which actin nucleation factors govern specific cellular functions.  To achieve a comprehensive understanding of the function of the actin cytoskeleton, we need to identify all of the nucleation factors, define their biochemical activities, and determine how their inactivation affects cellular functions.  These processes include membrane protrusion, cell motility, biosynthetic transport, endocytic trafficking, autophagy, and apoptosis.  In mammalian cells, actin filament networks are nucleated and organized by a macromolecule called the Arp2/3 complex, which works in conjunction with 8 nucleation-promoting factors from the Wiskott-Aldrich Syndrome Protein (WASP) family – WASP, N-WASP, WAVE1, WAVE2, WAVE3, WASH, WHAMM, and JMY – plus several additional atypical nucleation factors.  Other key actin nucleating proteins include 15 members of the Formin family and at least 6 tandem actin monomer binding nucleators from the Spire, Cobl, and Lmod families.

Although determining the basic functions of the actin cytoskeleton is a major component of our research, we are also very interested in understanding how these processes are altered during disease pathogenesis.  Due to its role at the foundation of so many cellular functions, the cytoskeleton is often targeted by pathogenic microbes.  One such bacterium is enterohemorrhagic Escherichia coli O157 (EHEC), a leading cause of bloody diarrhea and pediatric kidney failure in the US.  EHEC is able to modify many membrane remodeling pathways and reorganize cortical actin filaments into protrusive ‘pedestals’ during infection.  However, the mechanisms by which most EHEC effectors exploit their host protein targets to elicit these and other phenotypes are not well understood.  We are currently investigating how the cellular proteins that normally control cytoskeletal organization and membrane dynamics are taken over by several EHEC virulence factors, and how alterations in these host cell functions contribute to pathogenesis.