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Kazutoshi Mori and Peter Walter receive the 2014 Albert Lasker Basic Medical Research Award Corinne L. Williams J Clin Invest. 2014;124(10):4138-4142. https://doi.org/10.1172/JCI78419. News Cells are continuously faced with life-and-death decisions based on their ability to handle stressful situations. One indicator of stress is the accumulation of unfolded proteins within the ER, which induces a transcriptional cascade aimed at increasing the folding capacity of the ER. If the burden is too great and homeostasis cannot be restored, the response shifts from damage control to the induction of apoptotic pathways. This unfolded protein response (UPR) is conserved among all eukaryotes, and dysfunction in this pathway underlies many human diseases, including diabetes and cancer. The 2014 Albert Lasker Basic Medical Research award honors Kazutoshi Mori of Kyoto University and Peter Walter of the UCSF (Figure 1) for their contributions toward unraveling the pathways involved in mediating the complex cellular response to ER stress. A simple question In the 1970s, the identification of a set of proteins that were induced in response to viral transformation set the stage for understanding heat shock-independent cellular stress responses. These particular proteins were constitutively present in cells and notably increased in response to glucose deprivation (1) or agents that block post-translational glycosylation, such as tunicamycin. Based on this apparent glucose-dependent regulation, they became known as glucose-regulated proteins (GRPs). One of the most strongly induced proteins, GRP78, was found to localize to the ER, and soon after, researchers realized that GRP78 was […] Find the latest version: https://jci.me/78419/pdf NEWS The Journal of Clinical Investigation Kazutoshi Mori and Peter Walter receive the 2014 Albert Lasker Basic Medical Research Award Cells are continuously faced with life- part of a team led by Mary-Jane Gething was accepted as an exchange student at and-death decisions based on their ability and Joe Sambrook at the University of Vanderbilt University as part of the mas- to handle stressful situations. One indica- Texas Southwestern Medical Center at ter’s program in organic chemistry. As Wal- tor of stress is the accumulation of unfold- Dallas, transformed mammalian cells with ter recounted to the JCI, “I was adopted into ed proteins within the ER, which induces mutant forms of influenza hemagglutin the lab of Thomas Harris, where I studied a transcriptional cascade aimed at increas- (HA) and revealed that HA molecules that the synthesis of an alkaloid produced by ing the folding capacity of the ER. If the were unable to leave the ER induced tran- a fungus that grows on red clover in Ten- burden is too great and homeostasis cannot scription of the genes encoding BiP and nessee. When cows ingest the fungus it be restored, the response shifts from dam- other known GRPs. Moreover, the same causes them to slobber.” During his time age control to the induction of apoptotic transcriptional response that was induced at Vanderbilt, Walter found himself in a pathways. This unfolded protein response by the accumulation of mutant HA in the one-on-one meeting with Nobel laureate (UPR) is conserved among all eukaryotes, ER was recapitulated with tunicamycin Stanford Moore, who at the time was on and dysfunction in this pathway underlies many human diseases, including diabetes and cancer. The 2014 Albert Lasker Basic Medical Research award honors Kazutoshi Mori of Kyoto University and Peter Walter of the UCSF (Figure 1) for their contribu- tions toward unraveling the pathways involved in mediating the complex cellular response to ER stress. A simple question In the 1970s, the identification of a set of proteins that were induced in response to viral transformation set the stage for Figure 1. The recipients of the 2014 Albert Lasker Basic Medical Research Award. Kazutoshi Mori (left) of Kyoto University and Peter Walter (right) of the UCSF have been selected for their work iden- understanding heat shock-independent tifying key players of the UPR. cellular stress responses. These particu- lar proteins were constitutively present in cells and notably increased in response to glucose deprivation (1) or agents that block treatment (2). The revelation by Kozut- the Board of Trustees at Vanderbilt and a post-translational glycosylation, such as sumi and colleagues that the accumula- professor at The Rockefeller University. tunicamycin. Based on this apparent glu- tion of unfolded or misfolded proteins in “I can’t recall how a lowly student, such cose-dependent regulation, they became the ER results in a distinct transcriptional as myself, ended up having a one-on-one known as glucose-regulated proteins response gave rise to a simple question. meeting with Dr. Moore, but he strongly (GRPs). One of the most strongly induced “How are signals from the ER relayed to encouraged me to apply to the doctorate proteins, GRP78, was found to localize to the nucleus?” Two of the scientists that program at Rockefeller.” Walter applied the ER, and soon after, researchers real- provided answers to this question had and was put on the waiting list before finally ized that GRP78 was the same as a previ- backgrounds in chemistry and left their being accepted. After initially being turned ously identified protein, the immunoglob- home countries to join influential cell biol- down, Walter would eventually join Günter ulin heavy chain binding protein (BiP). BiP ogy labs in the United States. Blobel’s lab, a massively transformative was known to function as a chaperone and experience in his career. “It was a small lab bind both nascent and malformed pep- The draw of cell biology at the time that was just incredibly interac- tides in the ER, leading to the hypothesis After finishing his undergraduate degree tive and energetic, with many different proj- that the presence of unfolded or misfolded in chemistry in his native Germany, Peter ects going on. Many of Günter’s ideas were proteins underlies induction of the GRPs, Walter was encouraged to study abroad in highly contested and controversial, and he and not glucose deprivation per se. To test the United States. After an unsuccessful was a fighter out there for his ideas, with so this hypothesis, Yasunori Kozutsumi, as Fulbright Scholarship application, Walter much passion and conviction. However, he was also always capable of listening to data and changing his opinion as the landscape Reference information: J Clin Invest. 2014;124(10):4138–4142. doi:10.1172/JCI78419. changed. It is a wonderful thing to have a 4138 jci.org Volume 124 Number 10 October 2014 The Journal of Clinical Investigation NEWS goal and march toward it, then as the work brook lab had determined that yeast have a was proposed to be a protein kinase (8). progresses you make new discoveries and homologous response to unfolded proteins Mori et al. and Cox et al. both confirmed change the paradigm.” During his time in in the ER as well a BiP homolog (encoded that Ire1p is a transmembrane serine/ the Blobel lab, Walter became interested in by KAR2) (4), allowing this response to be threonine kinase and proposed that Ire1p how proteins are targeted to specific cellular evaluated in a genetically tractable model. is well poised to transmit signals from the locations throughout the cells and was part Mori set forth to understand the regula- lumen of the ER to the cytoplasm (6, 7). of the team that identified the signal recog- tory elements within the KAR2 promoter As a kinase, it was assumed that Ire1p nition particle (SRP), which directs nascent and identified three distinct elements that would transmit the unfolded protein signal peptides of secreted proteins to the ER (3). independently mediated constitutive, heat via phosphorylation of a downstream tar- Walter continued the work on intracellular shock–induced, and UPR-induced KAR2 get, ultimately activating a transcription targeting in his own lab at the UCSF. expression (5). The UPR element (UPRE) factor. The chase was on to identify the Kazutoshi Mori always knew that he within the KAR2 promoter turned out to downstream transcription factor responsi- wanted to be a scientist and recently told be a 22-bp sequence that when localized ble for transcription of UPR-induced genes. the JCI, “Although there was no atmo- upstream of a gene promotes expression of Walter and his group moved forward with a sphere of science in my family, it was my the gene in response to ER stress. high-copy suppressor screen, which would dream since childhood to be a PhD scien- At UCSF, Peter Walter had set up his identify genes able to overcome the defec- tist. My interest was driven by the comics, lab and was greatly influenced by his fellow tive UPR response in Ire1p mutants. After which I loved to read, such as Mighty Atom colleagues. As he told the JCI, “UCSF was the identification of Ire1p in 1993, Mori (aka Astro Boy) and Mach GoGoGo (aka a different environment. There was a lot was ready to return to Japan and secured Speed Racer). I found a bright future in sci- more communication between labs com- a position at the HSP Research Institute. ence and technology. I was also affected by pared to what I had experienced at Rock- As Mori recounted, “My new director, Dr. the movie Modern Times by Charlie Chap- efeller. There was a lot more discussion Takashi Yura, who had just retired from lin.” As an undergraduate, Mori was more and thought about genetics and structure. Kyoto University (where he investigated interested in chemistry and physics than Ira Herskowitz strongly promoted genetic heat shock response in E. coli), allowed biology; however, this would change after approaches in yeast, while Bob Stroud pro- me to continue working on the UPR.

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