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Published Online June 4, 2009
Science DOI: 10.1126/science.1172308

Reports

Submitted on February 16, 2009
Accepted on May 21, 2009

RIP3, an Energy Metabolism Regulator that Switches TNF-Induced Cell Death from Apoptosis to Necrosis

Duan-Wu Zhang 1, Jing Shao 1, Juan Lin 1, Na Zhang 1, Bao-Ju Lu 2, Sheng-Cai Lin 1, Meng-Qiu Dong 2, Jiahuai Han 1*

1 The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
2 The National Institute of Biological Sciences, Beijing, China.

* To whom correspondence should be addressed.
Jiahuai Han , E-mail: jhan{at}scripps.edu; jhan@xmu.edu.cn

Necrosis can be induced by stimulating death receptors with tumor necrosis factor (TNF) or other agonists; however, the underlying mechanism differentiating necrosis from apoptosis is largely unknown. We identified the protein kinase RIP3 as a molecular switch between TNF-induced apoptosis and necrosis in NIH3T3 cells, and found that RIP3 was required for necrosis in other cells. RIP3 did not affect RIP1-mediated apoptosis, but was required for RIP1-mediated necrosis and the enhancement of necrosis by the caspase inhibitor zVAD. By activating key enzymes of metabolic pathways, RIP3 regulated TNF-induced reactive oxygen species production, which partially accounts for RIP3’s ability to promote necrosis. Our data suggest that modulation of energy metabolism in response to death stimuli has an important role in the choice between apoptosis and necrosis.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
RIP Kinases Initiate Programmed Necrosis.
L. Galluzzi, O. Kepp, and G. Kroemer (2009)
J Mol Cell Biol 1, 8-10
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Science. ISSN 0036-8075 (print), 1095-9203 (online)