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J. Biol. Chem., Vol. 280, Issue 36, 31530-31536, September 9, 2005

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Interferon Induces NF-B-inducing Kinase/Tumor Necrosis Factor Receptor-associated Factor-dependent NF-B Activation to Promote Cell Survival^*

Chuan He Yang, Aruna Murti, and Lawrence M. Pfeffer

From the Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and the University of Tennessee Cancer Institute, Memphis, Tennessee 38163

Type I interferons (IFNs) play critical roles in the host defense by modulating the expression of various genes via the IFN-dependent activation of signal transducers and activators of transcription and NF-B (nuclear factor kappa B) transcription factors. Previous studies established that IFN/ activates NF-B to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which involves serine phosphorylation and degradation of IB. We now describe a second pathway by which IFNs activate NF-B that is independent of IB degradation. This pathway involves NF-B-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TRAF2) and results in IFN/-induced processing of the p100/NF-B2 precursor into p52. IFN/ stimulates NF-B DNA binding and NF-B-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-B activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-B activation and IFN-stimulated B-dependent transcription and IFN/-induced processing of the p100/NF-B2 precursor into p52. In contrast, PI3K does not mediate IFN/-induced p100 processing, although PI3K is involved in the pathway resulting in IB degradation. Moreover, whereas IFN promotes cell survival in lymphoblastoid cells, expression of dominant negative NIK and TRAF2 constructs enhances IFN-induced apoptosis. Our results for the first time place NIK and TRAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-B activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IB proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF.

Received for publication, March 21, 2005 , and in revised form, July 5, 2005.

^* This work was supported by National Institutes of Health Grant CA73753 (to L. M. P.) and by funds from the Muirhead Chair Endowment at the University of Tennessee Health Science Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Ave. (Rm. 530), Memphis, TN 38163. Tel.: 901-448-7855; Fax: 901-448-6979: E-mail: lpfeffer{at}utmem.edu.

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