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First published online September 15, 2004
doi: 10.1242/10.1242/jcs.01339

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ß-actin is required for mitochondria clustering and ROS generation in TNF-induced, caspase-independent cell death

¹ The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
² Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
³ Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

^* Authors for correspondence (e-mail: jhan{at}scripps.edu, lqxmllsy{at}hotmail.com)

Accepted 1 June 2004

Tumor necrosis factor (TNF)- induces caspase-independent cell death in the fibrosarcoma cell line L929. This cell death has a necrotic phenotype and is dependent on production of reactive oxygen species (ROS) in the mitochondria. To identify genes involved in this TNF-induced, ROS-dependent cell death pathway, we utilized retrovirus insertion-mediated random mutagenesis to generate TNF-resistant L929 cell lines and we subsequently identified genes whose mutations are responsible for the TNF-resistant phenotype. In one such resistant line, ß-actin was disrupted by viral insertion, and subsequent reconstitution of ß-actin expression levels in the mutant line Actin^mut restored its sensitivity to TNF. Resistance to TNF in Actin^mut cells is signal specific since the sensitivity to other death stimuli is either unchanged or even increased. Comparable NF-B activation and p38 phosphorylation in TNF-treated wild-type and Actin^mut cells also indicates that reduced expression of actin only selectively blocked some of the TNF-induced cellular changes. Actin cleavage involved in apoptosis does not occur in TNF-treated L929 cell death, as in HeLa cells. Consistent over-expression of a caspase-cleaved product, a 15 kDa actin fragment, had no effect on TNF-induced necrosis of L929 cell. By contrast, TNF-induced mitochondria clustering and ROS production were dramatically reduced in Actin^mut cells, indicating that actin-deficiency-mediated TNF resistance is most likely due to impaired mitochondrial responses to TNF stimulation. Our findings suggest that a full complement of actin is required for transduction of a cell death signal to mitochondria in TNF-treated L929 cells.

Key words: TNF, ß-actin, Necrosis, ROS

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