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.

Profile

Web Site URL

http://www.upr.biophys.kyoto-u.ac.jp/en/

A brief Biography

Education
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
Occupation
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

April 2005	The Fourth Annual Wiley Prize in Biomedical Sciences
October 2009	Canada Gairdner International Award
April 2010	Medal of Honor with Purple Ribbon from the Emperor
March 2012	Uehara Prize
January 2014	Asahi Prize
September 2014	Albert Lasker Basic Medical Research Award
September 2014	Shaw Prize in Life Science and Medicine
September 2015	2015 Thomson Reuters Citation Laureate
June 2016	Imperial Prize and Japan Academy Prize
December 2017	2018 Breakthrough Prize in Life Sciences

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.