Professor of Biophysics at the Graduate School of Science, Kyoto University, Japan
AsianScientist (June 17, 2015) – While DNA is the language of biological information, proteins are the workhorses of the cell, performing the functions that make life possible. But what happens when proteins become misfolded?
It turns out that nature has a built in quality control system: the unfolded protein response (UPR). Conserved from mammals all the way to yeast, the UPR is a suite of activities that help cells cope with misfolded proteins; stopping further protein translation and upregulating the production of protein folding assistants known as chaperones at low levels of cellular stress and driving the cell towards apoptosis when cellular stress is too high.
In 1993, Professor Kazutoshi Mori published a paper that identified IRE1 as a core component of the UPR in yeast. His subsequent work went on to detail the precise signaling pathways and mechanistic details of the UPR in mammals, work that was recognized with the 2014 Albert Lasker Basic Medical Research Award. Mori shared the prize with Professor Peter Walter, a fellow UPR pioneer based at the University of California, San Francisco.
Widely seen as a precursor the the Nobel Prize, Albert Lasker Basic Medical Research Award is given to scientists whose work has “provided techniques, information or concepts contributing to the elimination of major causes of disability and death.” Previous awardees who have gone on to win Nobel Prizes include Shinya Yamanaka (2009) and Aaron Ciechanover (2000).
Mori—whose personal research philosophy is to find out what’s really going on in our cells and bodies—shares with Asian Scientist Magazine how he made his discovery and the exciting applications of his research in fields such as cancer, Alzheimer’s disease and rare genetic conditions such as Wolcott-Rallison syndrome.
1. What were the experiences that made you decide to take a career in science, specifically in molecular biology?
I did not like biology in high school as the textbooks seemed descriptive. I felt I had to learn everything by heart. As a freshman at Kyoto University, most of my learning came from newspapers. I was amazed by the fact that the genetic code is conserved from E. coli to humans, which allowed scientists to produce human proteins in E. coli. I hoped for a bright future in biology. So, I switched my major from chemistry to biology.
2. Why is the unfolded protein response important for cells?
Proteins must gain correct tertiary and quaternary structures to fulfill their functions assigned by the genetic code. Secretory and transmembrane proteins important for cell-cell communication are folded and assembled in the endoplasmic reticulum (ER). Accumulation of unfolded/misfolded proteins in the ER activates the UPR. The cell cannot maintain the homeostasis of the ER without UPR. We cannot even be born without UPR.
3. What was the biological question guiding your research?
There have always been important questions to be answered. I wanted to know the mechanism of yeast UPR, the mechanism of mammalian UPR, how important is ATF6, why we have ten ER stress sensors, etc.
4. In what way did your discovery change the understanding of how cells respond to stress?
Professor Peter Walter and I unraveled the basic mechanisms of yeast UPR and I unraveled the basic mechanisms of mammalian UPR.
I also created ATF6 knockout mice and ATF6 knockout medaka fish to study its function in vivo.
5. What are some of the practical applications of your research?
We now know cancer cells are very sensitive to ER stress, because cancer cells need the UPR to survive under the very stressful situations of low oxygen and low nutrients. We will soon start the screening of chemicals which are able to kill cancer cells by inhibiting the UPR. From now, we will switch to both basic and applied research.
6. What would you say to scientists who question the validity of studies done in yeast and animal models in general?
The ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) is now known as the causal gene of the Wolcott-Rallison syndrome characterized by early infancy type I diabetes. This is a good example of how studies done in yeast and animal models help people (scientists) to understand the mechanism of disease development: The mammalian PERK was cloned by metabolic disease expert Professor David Ron at the University of Cambridge as an ER stress sensor which attenuates translation generally in response to ER stress. He used the information that PERK’s N-terminal ER luminal region might be similar to that of yeast IRE1, which I cloned using yeast genetic screening.
The PERK knockout mice Ron constructed suffered from diabetes, because PERK is critical for the maintenance of insulin-producing pancreatic β cells. The idea of ER stress and UPR is critical to understand the development of the Wolcott-Rallison syndrome.
7. Please share with us what your research group is currently working on. What do you hope to achieve in the next five to ten years?
The mammalian UPR consists of three pathways, IRE1, PERK and ATF6. Analyses of knockout mice showed the importance of UPR activation. PERK knockout mice suffer from diabetes because pancreatic β cells undergo apoptosis. IRE1 knockout causes embryonic lethality due to the failure of liver development. ATF6 knockout also causes embryonic lethality at a very early stage, which we found using the medaka fish system and was due to the failure of notochord development. So, we can usually survive if we can activate the UPR, but we still do not know why knockout of the ubiquitously expressed ER stress sensors IRE1, PERK and ATF6 causes these characteristic defects in different organs.
Further, yeast cells only have IRE1 as an ER stress sensor but we, human, have ten sensors. However, we do not know actually what is ER stress yet. What kinds of proteins are unfolded/misfolded under what kind of situations? We seek answers to such questions by investigating when and where ten ER stress sensors are activated during our normal development from zygote to adult using medaka fish. Then, we will characterize ER stress in various disease models to cure diseases.
In addition, some cells, such as insulin-producing pancreatic β cells, are very sensitive to ER stress but others, such as glucagon-producing pancreatic α cells, are resistant to ER stress. We want to know the basis for this difference.
8. What would you say has been the highlight of your research career?
After the publication of the IRE1 paper in 1993, I came back to Japan and obtained a temporary position at the HSP Research Institute. My new director Dr. Takashi Yura, who had just retired from Kyoto University, allowed me to continue working on the UPR. The next target was the transcription factor specific to yeast UPR. Yeast researchers usually carry out multicopy suppressor screening to obtain the next gene after isolation of yeast mutant cells (Walter did so). But Yura advised me not to employ multicopy suppressor screening, because Ire1 is a kinase and there may be a kinase cascade downstream of Ire1.
So, you may end up obtaining many many kinases but not the transcription factor you want. Because the HSP Research Institute focuses on transcription, you should think of a method by which you can obtain your transcription factor directly. It was a very difficult task, because I did not want to purify the factor biochemically. After struggling for one and a half years, I finally came up with the idea of one-hybrid screening, which, on hindsight, was the most important moment in my career. It worked very well and I identified the HAC1 gene. Again, Walter and I identified HAC1 independently in 1996.
9. What role do awards such as the Nobel Prize, Lasker Prize etc play in the career of a scientist?
One’s recognition and exposure increases dramatically. I was in newspapers after the receipt of the Canada Gairdner International Award in 2009. I was on TV after the receipt of the Lasker Award in 2014.
10. What is your personal research philosophy?
Let’s find out what is really going on in our cells and in our bodies.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Mori Research Laboratory.
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