Membrane Spanning and Subcellular Trafficking Mechanisms of a Viral Capsid Protein- Lessons from a Master Cell Biologist

PROJECT SUMMARY / ABSTRACT Throughout the course of coevolution within their host organisms, viruses have evolved to become masters of the cell- manipulating and exploiting cellular signaling, transport, and trafficking pathways. Studies of basic virology offer the prospect of illuminating cellular biology through the lens of a natural cell biologist, often (and historically) unveiling new aspects of cellular form and function. Here we propose work to elucidate the membrane spanning and subcellular trafficking mechanisms used by the human papillomavirus (HPV) L2 capsid protein during the course of early infection within endo/lysosomal, retrograde transport, and Golgi compartments. Here we will work to understand the role(s) of the local membrane microenvironment, membrane curvature and tension, ion flux, cellular gamma secretase, and specific L2 elements (amphipathic helix, transmembrane domain, C-terminal cell penetration peptide) in L2 membrane spanning. We have also recently discovered that a small peptide derived from cellular sorting nexin 1 (SNX1) potently blocks the retrograde trafficking of HPV, and we propose work to elucidate the inhibitory mechanisms of the peptide and unveil the role(s) of the cellular SNX-BAR family of sorting nexin proteins on L2 membrane spanning and retrograde trafficking of virus. Combined, this work will unveil new insight into cellular biology of protein-membrane interactions, protein transport across membranes, and vesicular trafficking.