A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses

Francis Ka Ming Chan, Joanna Shisler, Jacqueline G. Bixby, Martin Felices, Lixin Zheng, Michael Appel, Jan Orenstein, Bernard Moss, Michael J. Lenardo

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327 Scopus citations

Abstract

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein (RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2 -/-mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-XL, p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.

Original languageEnglish (US)
Pages (from-to)51613-51621
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number51
DOIs
StatePublished - Dec 19 2003

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    Chan, F. K. M., Shisler, J., Bixby, J. G., Felices, M., Zheng, L., Appel, M., Orenstein, J., Moss, B., & Lenardo, M. J. (2003). A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses. Journal of Biological Chemistry, 278(51), 51613-51621. https://doi.org/10.1074/jbc.M305633200