Title of Presentation

“Cell Death and Fate of Dead Cells”

Many extra, useless or harmful, cells are generated and die during animal development. In human adults, billions of senescent and activated cells die every day as part of the body’s natural processes. Cells that become damaged by microbial infection or mechanical stress also die. The cell death that occurs in the physiological setting is programmed, and is mediated by Apoptosis. Apoptosis is a clean process, in which cells are condensed and fragmented, and are engulfed by macrophages, without releasing their cellular materials. There are a group of cytokines that work as “death factors”. Death factors specifically bind their receptors on the cell surface, and trigger apoptotic cell death to kill the cells within hours. Apoptosis is mediated by proteases called “caspases” that cleave more than 500 cellular substrates. A DNase (CAD, or Caspase-activated DNase) is also activated in the downstream of caspases, and cleaves their own DNA into nucleosomal units. Dying cells secrete a “find me” signal, and expose an “eat me” signal on their surface. In response to the “find me” signal, macrophages approach to the dead cells, and recognize “phosphatidylserine” exposed on the dead cell’s surface as an “eat me” signal. Using sophisticated cell machinery, the macrophages ingest dead cells, direct them to lysosomes, and degrade their cellular components into basic biochemical building blocks: amino acids, nucleotides, fatty acids, and monosaccharides. These molecules will be released from the lysosomes and re-used to make new macromolecules. A defect in the apoptotic death process is one of the causes of cancers. While, inefficient dead-cell engulfment activates the immune system, causing systemic lupus erythematosus-type autoimmune diseases. If dead cell components are not properly degraded in macrophages, they activate the innate immunity, leading anemia and chronic arthritis via auto-inflammation. Here, I discuss how cells die and how dead cells are engulfed and degraded in macrophages.

References
1. Nagata S, Golstein P (1995) The Fas death factor. Science 267:1449-1456.
2. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619-630.
3. Nagata S. and Tanaka M (2017) Programmed cell death and the immune system. Nat. Rev. Immunol. 17, 333-340.
4. Nagata, S. Apoptosis and clearance of apoptotic cells. Annu. Rev. Immnunol. in press

Profile

Web Site URL

http://biochemi.ifrec.osaka-u.ac.jp/english/

A brief Biography

1972	Bachelor of Science, University of Tokyo
1977	Ph.D., Institute of Medical Science, University of Tokyo
1977	Post-Doctoral Fellow at Institute of Molecular Biology Institute of Molecular Biology, University of Zürich
1982	Assistant Professor, Institute of Medical Science, University of Tokyo
1987	Head, Department of Molecular Biology, Osaka Bioscience Institute
1995	Professor, Faculty of Medicine, Osaka University
2007	Professor, Graduate School of Medicine, Kyoto University
2010	Vice-Dean, Graduate School of Medicine, Kyoto University
2015	Specially Appointed Professor, Immunology Frontier Research Center (IFReC), Osaka University
2017	Distinguished Professor, Osaka University

Academic association board member, journal editorial board member, etc.

2004–2005	Advisory Member of Central Council for Education (Subdivision on Universities), Ministry of Education, Culture, Sports, Science and Technology
2008–2014	Member of the 21st Science Council of Japan (SCJ)
1995–2009	Councilor, Japanese Cancer Association (JCA)
2000–2002	Board Directors, Japanese Biochemical Society (JBS)
1999–2002	Board Member, Japanese Society for Immunology (JSI)
2004–2007	Board Member, Japanese Society for Immunology (JSI)
2005–2006	President, Japanese Biochemical Society (JBS)
2007–2008	President, Molecular Biology Society of Japan (MBSJ)
1994–present	Member of the Editorial Board of Cell Death & Differentiation
1998–present	Member of the Editorial Board of Immunity
2000–2003	Member of the Editorial Board of Science
2001–present	Member of the Editorial Board of Cancer Cell, etc.

Details of selected Awards and Honors

1994. 11	Emil von Boehring Prize (Marburg University, Germany)
1995. 10	Robert Koch Award (Koch Foundation, Germany)
1997. 1	Le Prix Laccasagne (French National Cancer League, France)
2000. 6	Imperial Prize and Japan Academy Prize (Japan Academy, Tokyo)
2001. 11	Person of Cultural Merit (Japanese Government, Tokyo)
2011. 1	Member of Japan Academy (Japan Academy, Tokyo)
2012. 4	Ehrendoctoren (Universität Zürich, Switzerland)
2012. 12	Debrecen Award (Debrecen University, Hungary)
2013. 11	Keio Medical Science Prize (Keio University, Tokyo)
2015. 4	Foreign Associate of the National Academy of Science of USA

A list of selected Publications

Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y and Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233-243.

Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA and Nagata S (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314-317.

Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T and Nagata S (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364: 806-809.

Suda T, Takahashi T, Golstein P and Nagata S (1993) Molecular cloning and expression of the Fas ligand: a novel member of the tumor necrosis factor family. Cell 75: 1169-1178.

Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A and Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD. Nature 391: 43-50.

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A and Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417: 182-187.

Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H and Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443: 998-1002.

Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T., and Nagata, S. (2007) Identification of Tim-4 as a phosphatidylserine receptor. Nature 450: 435-439.

Suzuki, J., Denning, DP., Imanishi, E., Horvitz, HR. and Nagata, S. (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341: 403-406.

Segawa, K., Kurata, S., Yanagihashi, Y., Brummelkamp, T., Matsuda, F., and Nagata, S. (2014) Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164-1168