Protein homeostasis (proteostasis) networks, along with fundamental biophysics, govern protein evolution. Acquisition of adaptive amino acid mutations during evolution is often kinetically or thermodynamically destabilizing to proteins. Chaperones from the proteostasis machinery can rescue these destabilizing mutations when they occur in endogenous client proteins. By combining new methods for chemical perturbation of proteostasis machinery with evolutionary biology techniques, we discovered that this phenomenon has profound impact on the ability of RNA viruses to adapt to environmental and immune system pressures. In particular, we show that influenza hijacks host chaperones to address folding defects that viral proteins acquire as they evolve to escape the hostâs innate and adaptive immune systems. The dependence of viruses on their hostâs protein folding network makes them highly vulnerable to immune suppression when folding assistance is limited. Host chaperones, therefore, play a central role in facilitating viral adaptation at the hostâpathogen interface, a finding with potentially far-reaching implications for viral host-switching and drug/antibody resistance development. Currently, we are investigating how these types of phenomena impact the evolution of other disease-relevant genes, including oncogenes.
Matthew Shoulders (MIT)