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KAROLINSKA RESEARCH LECTURES AT NOBEL FORUM SPRING 2012

//KAROLINSKA RESEARCH LECTURES AT NOBEL FORUM SPRING 2012

Thursday March 29

Professor Shigekazu Nagata

Department of Medical Chemistry

Graduate School of Medicine, Kyoto University, Kyoto, Japan

LINK TO LAB WEBPAGE

Host:Professor Boris Zhivotovsky, IMM, KI

Title: Apoptosis and its failure

Abstract

Every day, several billions of cells die in our bodies and are cleared by phagocytes or macrophages. In most cases (at least in physiological settings), the cells die via a process called “apoptosis”. We showed that apoptosis can be triggered by binding of a factor (death factor, Fas ligand) to its receptor, Fas. In this process, a cascade of caspases, cysteine-proteases, is activated to cleave several hundreds of cellular substrates. This causes morphological changes of the cells and degradation of chromosomal DNA into nucleosomal units that are hallmarks of the apoptosis. The asymmetrical distribution of phospholipids on the plasma membrane is disrupted in the apoptotic cells, and the phosphatidylserine exposed on the cell surface works as an “eat me” signal(s) for phagocytes. The “eat me” signals are recognized by specific molecules expressed in macrophages for engulfment, and all dead cell components are degraded in their lysosomes. Failure of the apoptotic process causes various diseases. A deficiency of Fas or Fas ligand causes accumulation of activated lymphocytes, leading to lymphadenopathy and autoimmune diseases, while the exaggeration of the Fas ligand-induced apoptosis causes tissue damage. When dead cells are not efficiently engulfed by macrophages, the immune system is activated, leading to SLE-type autoimmune disease. Whereas, when cellular components of dead cells are not promptly degraded in the macrophages, undigested materials activate the macrophages, and induce strong inflammation. I will discuss about the apoptotic cell death, signal transduction, and the diseases caused by its failure.

1.Nagata, S., Apoptosis by death factor. Cell 88, 355-365 (1997).

2.Nagata, S., Hanayama, R., & Kawane, K., Autoimmunity and the clearance
of dead cells. Cell 140, 619-630 (2010).

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