TNF-Induced Activation of the Nox1 NADPH Oxidase and Its Role in the Induction of Necrotic Cell Death

Kim, Y. S., et al. 2007. Mol. Cell. 26, 675-687

Speaker: Yi Wang (王壹)                         Time: 15:10~16:00, Oct. 3, 2007

Commentator: Dr. Nan-Shan Chang (張南山博士)       Place: Room 601

Abstract:

   Tumor necrosis factor (TNF), an immunoregulator, involves in a variety of cellular responses, including cell apoptosis and necrosis. TNF performs its biological function through TNF receptor (TNFR) (1). In TNF-induced apoptotic cell death, the molecular mechanism has been widely elucidated. However, it is still unknown in the mechanism of TNF-induced necrotic cell death. The generation of respiratory oxygen species (ROS) by TNF-activated NADPH oxidase Nox2/gp91 is demonstrated in phagocytic and vascular cells (2). Since ROS plays a critical role in TNF-induced cell death (3), in the present paper, the authors hypothesize that activating Nox1 by TNF is indispensable for ROS-mediated necrosis in non-phagocytic cells. Results showed that TNF induced ROS production followed by the induction of necrotic cell death in murine fibrosarcoma L929 cells. Further data found that Nox1 particularly regulated ROS generation in L929 cells in response to TNF. Actually, TNF induced the formation of complex containing TNF receptor-associated death domain (TRADD), receptor-interacting protein 1 (RIP1), Rac1, and Nox1. Results showed that RIP1 was known to recruit Nox1 into the complex. They further found that NOXO1, a regulator of Nox1 activation, was associated with TRADD following TNF treatment.  Destruction of TRADD and Rac1 blocked Nox1 activity to reduce ROS generation and necrotic cell death. Further results showed that ROS prolonged JNK activation and contributed to TNF-induced necrosis. Taken together, these results demonstrate that Nox1 mediates TNF-induced necrotic cell death.

References:

1.          Chen, G. and D. V. Goeddel. 2002. TNF-R1 signaling: a beautiful pathway. Science. 296, 1634-1635.

2.          Lambeth, J. D. 2004. Nox enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 8, 181-189.

3.          Lin, Y., et al. 2004. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J. Biol. Chem. 279, 10822-10828.

*Presentation in English