Biochemistry, Cell Biology
University of California, San Francisco
Dr. Walter is also a distinguished professor in the Department of Biochemistry and Biophysics at the University of California, San Francisco.
The Unfolded Protein Response and Beyond
Peter Walter is focused on finding molecular answers to fundamental questions in cell biology. To that end, his lab studies how cells control the quality of their proteins and organelles during homeostasis, and in response to internal and external stresses.
Over the years, Walter’s lab group has identified cellular machinery and mechanisms that ensure proper protein synthesis, folding, and targeting. They have also uncovered pathways that allow organelles to communicate and regulate their abundance, such as the unfolded protein response – a quality control system that adjusts the endoplasmic reticulum’s capacity according to need. Historically, much of the lab’s work started in yeast and established key principles that the group then extended to mammalian systems.
The Walter lab’s current focus is on understanding how rewiring of basic and phylogenetically conserved processes of protein quality control can lead to, or prevent, the progression of disease. In this quest, the group uses a diverse array of approaches – ranging from biophysics and biochemistry to classical and chemical genetics – to fuel the search for fundamental discoveries and their application to disease models.
Grants from the National Institutes of Health and industry provided partial support for these projects.
Inside cells, newly made proteins pass through a maze-like structure called the endoplasmic reticulum (ER), where they are folded into their final shapes before being shipped to precise destinations. The ER enforces strict quality control standards to ensure that defective or misfolded proteins don’t slip through. Peter Walter is trying to elucidate the signals that tell the cell’s nucleus when the ER is overloaded. If these communications go awry, neurons could die inappropriately, leading to neurodegenerative disease, or menacing cells could be kept alive, causing cancer.
Walter’s scientific path began in the 1960s, when he spent hours tinkering with chemicals at his parents’ Drogerie (a store that sells nonprescription medicines and household products) in West Berlin, Germany. His explorations in the family shop led Walter to decide by age 12 that he would major in chemistry. However, the science training he got as an undergraduate at Free University of Berlin was unsatisfying. The lab experiments were too prescribed, Walter recalls. Determined to improve his English so he could read important biochemistry papers, Walter spent nine months in Nashville, Tennessee, working on the biosynthesis of a fungal alkaloid in Tom Harris’s lab at Vanderbilt University.
He remained in the U.S. after his fellowship ended, enrolling in a PhD program at Rockefeller University in the late 1970s. There, Walter worked with Günter Blobel, an HHMI investigator and winner of the 1999 Nobel Prize in Physiology or Medicine for his discovery of the mechanisms that proteins use to find their correct locations within the cell. Blobel had postulated that newly synthesized proteins contain built-in signals that direct them to their proper destinations, but without direct evidence, many scientists dismissed his idea. Walter provided such evidence by purifying the six proteins and the bit of RNA that comprise the signal recognition particle (SRP).
After Walter started his own lab at the University of California, San Francisco, in 1983, he made a deliberate shift from his research at Rockefeller. At the time, scientists knew that when misfolded proteins accumulate, the cell makes more ER. It was also clear that this compensatory activity is triggered by changes in gene expression in the cell’s nucleus. By the early 1990s, Walter’s team had uncovered the set of molecules that transmits this information between the ER and the nucleus. Called the “unfolded protein response” (UPR), this quality control system senses when misfolded proteins accumulate and spurs the cell to make more ER. The UPR “makes life-or-death decisions for cells. If misfolded proteins in the ER persist, cells kill themselves,” explains Walter.
Through a 2008 Hughes Collaborative Innovation Award – a program designed to support team projects of ambitious scope – Walter and colleagues synthesized small molecules that can regulate the UPR. Now the researchers are probing how the UPR functions in various disease models, in the hope of one day tweaking the system to help patients.
Walter’s pioneering research on the UPR has earned him a growing list of accolades – including a Shaw Prize and a Lasker Award in 2014, and the 2015 Vilcek Prize in Biomedical Science, which recognizes creative contributions of immigrants.