Interferonα Activates NF-κB in JAK1-deficient Cells through aTYK2-dependentPathway

Ziyun Du,Chuan He Yang,William J. Valentine,Lawrence M. Pfeffer,Aruna Murti

doi:10.1074/jbc.m413721200

Ziyun Du, Chuan He Yang + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m413721200

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Abstract

In addition to activating members of the STAT transcription factor family, interferon alpha/beta (IFNalpha/beta) activates the NF-kappaB transcription factor. To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-kappaB activation by IFN, we examined NF-kappaB activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH), IFN activates STAT1, STAT2, and STAT3, as well as NF-kappaB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells, IFN induces NF-kappaB activation and NF-kappaB dependent gene transcription but does not activate these STAT proteins and has no effect on STAT-dependent gene transcription. Expression of a catalytically inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-kappaB activation by IFN. Moreover, IFN does not promote NF-kappaB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-kappaB signaling pathway. In the IFN signaling pathway leading to STAT activation, both JAK1 and TYK2 are essential, whereas NF-kappaB activation requires only TYK2.

Highlights

IFNs1 are a family of multifunctional cytokines that block viral infection, inhibit cell proliferation, and modulate cell differentiation
IFN Induces Signal transducers and activators of transcription (STAT) Activation in Parental 2fTGH Cells but Not in JAK1Ϫ Mutant Fibrosarcoma Cells—The JAK1 and TYK2 tyrosine kinases mediate the tyrosine phosphorylation of cytoplasmic STAT proteins, which is essential for their nuclear translocation and DNA binding activity
Lysates prepared from control or IFN␣-treated 2fTGH and JAK1-deficient (JAK1Ϫ) cells were immunoblotted with immunoaffinitypurified anti-STAT antibodies and anti-STAT phosphospecific antibodies

Summary

Introduction

IFNs1 are a family of multifunctional cytokines that block viral infection, inhibit cell proliferation, and modulate cell differentiation. To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-␬B activation by IFN, we examined NF-␬B activation in JAK1-deficient mutant human fibrosarcoma cells. Expression of a catalytically inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-␬B activation by IFN.

Results

Conclusion