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

Research output: Contribution to journalArticlepeer-review


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
Issue number51
StatePublished - Dec 19 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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