Role of Cyclophilin B in Activation of Interferon Regulatory Factor-3

Yoko Obata,Kazuo Yamamoto,Masanobu Miyazaki,Kunitada Shimotohno,Shigeru Kohno,Toshifumi Matsuyama

doi:10.1074/jbc.m501684200

Yoko Obata, Kazuo Yamamoto + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m501684200

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Abstract

IRF-3 is a member of the interferon regulatory factors (IRFs) and plays a principal role in the induction of interferon-beta (IFN-beta) by virus infection. Virus infection results in the phosphorylation of IRF-3 by IkappaB kinase epsilon and TANK-binding kinase 1, leading to its dimerization and association with the coactivators CREB-binding protein/p300. The IRF-3 holocomplex translocates to the nucleus, where it induces IFN-beta. In the present study, we examined the molecular mechanism of IRF-3 activation. Using bacterial two-hybrid screening, we isolated molecules that interact with IRF-3. One of these was cyclophilin B, a member of the immunophilins with a cis-trans peptidyl-prolyl isomerase activity. A GST pull-down assay suggested that one of the autoinhibition domains of IRF-3 and the peptidyl-prolyl isomerase domain of cyclophilin B are required for the binding. A knockdown of cyclophilin B expression by RNA interference resulted in the suppression of virus-induced IRF-3 phosphorylation, leading to the inhibition of the subsequent dimerization, association with CREB-binding protein, binding to the target DNA element, and induction of IFN-beta. These findings indicate that cyclophilin B plays a critical role in IRF-3 activation.

Highlights

Interferon regulatory factors (IRF(s))1 are a family of transcription factors that regulate a variety of biological events, including innate immunity
We demonstrate the interaction of interferon regulatory factors (IRFs)-3 with cyclophilin B (CypB), an immunophilin with cis-trans peptidyl-prolyl isomerase and chaperone-like activities [15]
The present in vitro analysis suggests that autoinhibition domain of IRF-3 and the catalytic domain bearing the peptidyl-prolyl isomerase activity of CypB are required for the interaction

Summary

Introduction

Interferon regulatory factors (IRF(s))1 are a family of transcription factors that regulate a variety of biological events, including innate immunity. A knockdown of cyclophilin B expression by RNA interference resulted in the suppression of virus-induced IRF-3 phosphorylation, leading to the inhibition of the subsequent dimerization, association with CREB-binding protein, binding to the target DNA element, and induction of IFN-␤.

Results

Conclusion