Peter Walter, PhD
Distinguished Investigator, Altos Labs, Bay Area Institute of Science
Professor Emeritus, Department of Biochemistry & Biophysics, University of California, San Francisco

From its birth in the cradle of the ribosome to its demise in the fangs of proteolytic enzymes, a protein continuously explores different folding states. In most cell compartments, molecular sensors carefully monitor protein folding and instruct down-stream effectors to take corrective actions as needed. In response, cells can make adjustments to their protein folding and degradation machineries to stay in a healthy state of homeostasis. If protein folding defects occur and cannot be corrected in a sufficient and timely manner, cells induce suicide programs. Programmed cell death is thought to protect an organism from malfunctioning rogue cells that result from an accumulation of defective protein. In various pathologies, the life/death balance can inappropriately err on either side: killing cells that would be beneficial if kept alive, or, alternatively, inappropriately protecting dangerous, disease propagating cells. Studies of the regulation of proteostasis now emerge as focal points of foundational basic research that powerfully connects to a wide spectrum of unmet clinical needs.

I will discuss advances in our recent efforts to understand the molecular details of the unfolded protein and integrated stress responses (UPR and ISR), both conserved and intertwined signaling networks that survey the protein folding status in the endoplasmic reticulum and various cytoplasmic stress conditions. The development of small, drug-like molecules that selectively target components in these signaling networks has opened promising new therapeutic opportunities in areas as divergent as cancer, neurodegeneration, diabetes, inflammation, aging, and cognition. As such, the UPR and ISR emerge as examples of the power of fundamental cell biological discoveries to address problems of immense clinical and societal impact.