Interferon induces NF-κB-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-κB activation to promote cell survival

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/ Akt pathway, which involves serine phosphorylation and degradation of Iκbα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TKAF2) and results in IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription and IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI3K does not mediate IFNα/β-induced p100 processing, although PI3K is involved in the pathway resulting in IκBα 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 TBAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IκBα proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF.

Original languageEnglish (US)
Pages (from-to)31530-31536
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number36
DOIs
StatePublished - Sep 9 2005

Fingerprint

Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
NF-kappa B
Interferons
Cell Survival
Phosphotransferases
Chemical activation
Cells
Phosphatidylinositol 3-Kinase
TNF Receptor-Associated Factor 2
Transcription
Processing
NF-kappa B kinase
Degradation
Transcription Factors
Proteolysis
Signal transduction
Interferon Type I
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{971bd781ef1748b89f9c79479c63ac8e,
title = "Interferon induces NF-κB-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-κB activation to promote cell survival",
abstract = "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-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/ Akt pathway, which involves serine phosphorylation and degradation of Iκbα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TKAF2) and results in IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription and IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI3K does not mediate IFNα/β-induced p100 processing, although PI3K is involved in the pathway resulting in IκBα 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 TBAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a {"}canonical{"} pathway of IκBα proteolysis mediated by PI3K/Akt and a {"}noncanonical{"} pathway of p100 processing mediated by NIK/TRAF.",
author = "Chuan Yang and Aruna Murti and Lawrence Pfeffer",
year = "2005",
month = "9",
day = "9",
doi = "10.1074/jbc.M503120200",
language = "English (US)",
volume = "280",
pages = "31530--31536",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "36",

}

TY - JOUR

T1 - Interferon induces NF-κB-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-κB activation to promote cell survival

AU - Yang, Chuan

AU - Murti, Aruna

AU - Pfeffer, Lawrence

PY - 2005/9/9

Y1 - 2005/9/9

N2 - 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-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/ Akt pathway, which involves serine phosphorylation and degradation of Iκbα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TKAF2) and results in IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription and IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI3K does not mediate IFNα/β-induced p100 processing, although PI3K is involved in the pathway resulting in IκBα 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 TBAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IκBα proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF.

AB - 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-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/ Akt pathway, which involves serine phosphorylation and degradation of Iκbα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TKAF2) and results in IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription and IFNα/β-induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI3K does not mediate IFNα/β-induced p100 processing, although PI3K is involved in the pathway resulting in IκBα 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 TBAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IκBα proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF.

UR - http://www.scopus.com/inward/record.url?scp=24744469009&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24744469009&partnerID=8YFLogxK

U2 - 10.1074/jbc.M503120200

DO - 10.1074/jbc.M503120200

M3 - Article

C2 - 16009713

AN - SCOPUS:24744469009

VL - 280

SP - 31530

EP - 31536

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 36

ER -