5th Kyoto University-Inamori Foundation Joint Kyoto Prize Symposium
July 22, 2018

Theme “Balance between Construction and Destruction in Life”

Kazutoshi Mori

Kazutoshi Mori

Professor, Graduate School of Science, Kyoto University
Endoplasmic reticulum, molecular chaperone, protein folding, protein degradation intracellular signaling, gene expression

Title of Presentation

“Unfolded protein response: cellular response that controls quality of proteins”

The basic unit of an organism is the cell. A human being is made up of as many as 60 trillion cells. What is inside a cell? Our body contains various organs each with its own role: for example, the lungs for breathing and the heart for blood circulation. Similarly, a cell contains many little organs each with their individual roles. My research interest, endoplasmic reticulum, is one of these little ‘organs in a cell’ termed organelles that serves as a protein factory.

What is protein? In general, proteins are known to be one of the three major nutrients, together with carbohydrates and fats. At the cellular level, proteins are important substances that exist as the second largest amount of substance in a cell after water. It is not an exaggeration to say that we live because proteins work properly.

Let me take diabetes as an example. Diabetes is not caused by high urine sugar; when blood sugar (blood glucose level) is continuously high, sugar leaks out to the urine. It also damages blood vessels, which triggers various symptoms.

Everyone gets higher blood sugar after a meal; however, it goes down after a while because a protein called insulin is released from the pancreas into the blood. When this insulin (key) enters the insulin receptor (keyhole) and turns in it — like a car engine starting — liver cells and muscle cells take sugar from the blood, which reduces blood sugar.

A key and a keyhole have a specific shape for a one-to-one correspondence. For the proper function of a protein, its shape is important. A protein is made up of a sequence of amino acids, like beads on a wire. The shape of the ‘key’ is formed by the wire frame of this sequence. The wirework is done in the endoplasmic reticulum, a ‘factory in a cell’. This factory is quite remarkable and works hard; however, it sometimes fails and makes a greater number of defective products than usual. This state is called endoplasmic reticulum stress. My two supervisors at the University of Texas (USA) had discovered that a cell has a restorative force that can recover from this worsened state. Under their supervision, I started research to elucidate the mechanism of this force (the endoplasmic reticulum stress response) 29 years ago and was the first to discover a sensor molecule that detects a worsened condition in the endoplasmic reticulum. Since I returned to Japan, I have been continuously working to reveal how this amazing restorative force works. I will explain the results and significance of my work in simple terms.

Presentation Movie


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A brief Biography
March 1981 Graduated from the Faculty of Pharmaceutical Sciences, Kyoto University
April 1981
– March 1983
Master course student of the Graduate School of Pharmaceutical Sciences, Kyoto University
April 1983
– March 1985
Doctoral course student of the Graduate School of Pharmaceutical Sciences, Kyoto University
September 1987 Received Ph.D. from Kyoto University
April 1985
– March 1989
Instructor, Gifu Pharmaceutical University, Gifu, Japan
April 1989
– September 1993
Postdoctoral Fellow, University of Texas Southwestern Medical Center at Dallas, USA (supervised by Drs. M.-J. Gething and J. Sambrook)
October 1993
– March 1996
Deputy Research Manager, HSP Research Institute, Kyoto, Japan
April 1996
– March 1999
Research Manager, HSP Research Institute, Kyoto, Japan
April 1999
– October 2003
Associate Professor, Graduate School of Biostudies, Kyoto University, Japan
November 2003
– present
Professor, Department of Biophysics, Graduate School of Science, Kyoto University, Japan
Details of selected Awards and Honors
A list of selected Publications

Molecular Biology inside the Cell (Kodansha Bluebacks)

A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus. K. Mori, W. Ma, M.-J. Gething, and J. Sambrook, Cell, 74, 743-756, 1993.

Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. K. Haze, H. Yoshida, H. Yanagi, T. Yura, and K. Mori, Mol. Biol. Cell, 10, 3787-3799, 1999.

XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. H. Yoshida, T. Matsui, A. Yamamoto, T. Okada, and K. Mori, Cell, 107, 881-891, 2001.

A time-dependent phase shift in the mammalian unfolded protein response. H. Yoshida, T. Matsui, N. Hosokawa, R. J. Kaufman, K. Nagata, and K. Mori, Dev. Cell, 4, 265-271, 2003.

Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. K. Yamamoto, T. Sato, T. Matsui, M. Sato, T. Okada, H. Yoshida, A. Harada and K. Mori, Dev. Cell, 13, 365-376, 2007.

ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish. T. Ishikawa, T. Okada, T. Ishikawa-Fujiwara, T. Todo, Y. Kamei, S. Shigenobu, M. Tanaka, T. L. Saito, J. Yoshimura, S. Morishita, A. Toyoda, Y. Sakaki, Y. Taniguchi, S. Takeda and K. Mori, Mol. Biol. Cell, 24, 1387-1395, 2013.

EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. S. Ninagawa, T. Okada, Y. Sumitomo, Y. Kamiya, K. Kato, S. Horimoto, T. Ishikawa, S. Takeda, T. Sakuma, T. Yamamoto and K. Mori, J. Cell Biol., 206, 347-356, 2014.

Forcible Destruction of Severely Misfolded Mammalian Glycoproteins by the Non-glycoprotein ERAD Pathway. S. Ninagawa, T. Okada, Y. Sumitomo, S. Horimoto, T. Sugimoto, T. Ishikawa, S. Takeda, T. Yamamoto, T. Suzuki, Y. Kamiya, K. Kato and K. Mori, J. Cell Biol., 211, 775-784, 2015.

UPR Transducer BBF2H7 Allows Export of Type II Collagen in a Cargo- and Developmental Stage-Specific Manner. T. Ishikawa, T. Toyama, Y. Nakamura, K. Tamada, H. Shimizu, S. Ninagawa, T. Okada, Y. Kamei, T. Ishikawa-Fujiwara, T. Todo, E. Aoyama, M. Takigawa, A. Harada and K. Mori, J. Cell Biol., 216, 1761-1774, 2017.