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

• Published in: The Journal of biological chemistry Vol. 278; no. 51; pp. 51613 - 51621
• Main Authors: Chan, Francis Ka-Ming, Shisler, Joanna, Bixby, Jacqueline G., Felices, Martin, Zheng, Lixin, Appel, Michael, Orenstein, Jan, Moss, Bernard, Lenardo, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.12.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, CD - physiology; Caspase 8; Caspase 9; Caspases - pharmacology; Humans; Jurkat Cells; Mice; Mice, Knockout; Necrosis; Proteins - immunology; Proteins - metabolism; Proteins - physiology; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - pharmacology; Vaccinia - immunology; Vaccinia - pathology; Vaccinia virus; Virus Diseases - immunology; Virus Diseases - pathology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305633200

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.