Virus-triggered Ubiquitination of TRAF3/6 by cIAP1/2 Is Essential for Induction of Interferon-β (IFN-β) and Cellular Antiviral Response

Ai-Ping Mao,Shu Li,Bo Zhong,Ying Li,Jie Yan,Qi Li,Chengwen Teng,Hong-Bing Shu

doi:10.1074/jbc.m109.071043

Abstract

Viral infection causes activation of transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and cellular antiviral response. Here we show that knockdown of the E3 ubiquitin ligases cIAP1 and cIAP2 markedly inhibited virus-triggered activation of IRF3 and NF-kappaB as well as IFN-beta induction. Knockdown of cIAP1 and cIAP2 also inhibited cytoplasmic dsRNA-triggered cellular antiviral response. Endogenous coimmunoprecipitation experiments indicated that viral infection caused recruitment of cIAP1 and cIAP2 to TRAF3, TRAF6, and VISA. Furthermore, we demonstrated that cIAP1- and cIAP2-mediated virus-triggered ubiquitination of TRAF3 and TRAF6. These findings suggest that virus-triggered ubiquitination of TRAF3 and TRAF6 by cIAP1 and cIAP2 is essential for type I IFN induction and cellular antiviral response.

Highlights

Signaling pathways responsible for virus-triggered IFN induction have been extensively investigated during the past decade
We found that the E3 ubiquitin ligases cIAP1 and cIAP2 caused TRAF3 ubiquitination following viral infection and this is essential for virus-triggered IRF3 activation as well as IFN-␤ induction
The level of TRAF3 at the mitochondria was unchanged before and after viral infection (Fig. 4D), suggesting that cIAP1 and TRAF3 are not recruited to the mitochondria as a preformed complex, instead, viral infeccIAP1/2 Are Essential for Virus-triggered Signaling tion occurred at a later stage (Ͼ9 h after viral infection). These results suggest that Lys-48- and Lys-63-linked ubiquitination of TRAF3 and TRAF6 induced by viral infection is temporally regulated

Summary

Introduction

Signaling pathways responsible for virus-triggered IFN induction have been extensively investigated during the past decade. We found that the E3 ubiquitin ligases cIAP1 and cIAP2 caused TRAF3 ubiquitination following viral infection and this is essential for virus-triggered IRF3 activation as well as IFN-␤ induction. Knockdown of cIAP1 and cIAP2 inhibited SeV-induced activation of the IFN-␤ promoter in human primary dendritic cells (DCs) (Fig. 1D).

Results

Conclusion