Pivotal role for the ESCRT-II complex subunit EAP30/SNF8 in IRF3-dependent innate antiviral defense.
Pivotal role for the ESCRT-II complex subunit EAP30/SNF8 in IRF3-dependent innate antiviral defense.
复制标题
DOI：
10.1371/journal.ppat.1006713
复制
发表时间：
2017-10
期刊：
影响因子：
6.7
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Kumthip K;Yang D;Li NL;Zhang Y;Fan M;Sethuraman A;Li K
The activation of interferon (IFN)-regulatory factor-3 (IRF3), characterized by phosphorylation and nuclear translocation of the latent transcription factor, is central to initiating innate antiviral responses. Whereas much has been learned about the upstream pathways and signaling mechanisms leading to IRF3 activation, how activated IRF3 operates in the nucleus to control transcription of IFNs remains obscure. Here we identify EAP30 (a.k.a, SNF8/VPS22), an endosomal sorting complex required for transport (ESCRT)-II subunit, as an essential factor controlling IRF3-dependent antiviral defense. Depletion of EAP30, but not other ESCRT-II subunits, compromised IRF3-dependent induction of type I and III IFNs, IFN-stimulated genes (ISGs) and chemokines by double-stranded RNA or viruses. EAP30, however, was dispensable for the induction of inflammatory mediators of strict NF-κB target. Significantly, knockdown of EAP30 also impaired the establishment of an antiviral state against vesicular stomatitis virus and hepatitis C virus, which are of distinct viral families. Mechanistically, EAP30 was not required for IRF3 activation but rather acted at a downstream step. Specifically, a fraction of EAP30 localized within the nucleus, where it formed a complex with IRF3 and its transcriptional co-activator, CREB-binding protein (CBP), in a virus-inducible manner. These interactions promoted IRF3 binding to target gene promoters such as IFN-β, IFN-λ1 and ISG56. Together, our data describe an unappreciated role for EAP30 in IRF3-dependent innate antiviral response in the nucleus. The induction of IFN antiviral response is a hallmark of immediate host immune responses to viral infections. In a majority of cell types, eliciting this intrinsic defense mechanism depends on activation of IRF3, characterized by C-terminal phosphorylation, dimerization and subsequent nuclear translocation of the latent transcription factor. While the molecular pathways and signaling events leading to IRF3 activation have been extensively studied, how activated IRF3 operates in the nucleus to trigger antiviral gene expression remains murky. In this study, we reveal that EAP30, an endosomal sorting complex required for transport (ESCRT)-II subunit, is a novel, pivotal factor controlling IRF3-dependent antiviral defense. We demonstrate that a fraction of EAP30 resides in the nucleus, where it forms a complex with IRF3 and its transcriptional co-activator, CBP, in response to viral insults. These interactions are essential for IRF3 binding to its target gene promoters and subsequent transcription of antiviral genes including those encoding type I and III IFNs and IFN-stimulated genes. Our data unveil a previously unappreciated role for EAP30 in facilitating IRF3-mediated antiviral response in the nucleus and raise the possibility that this novel function of EAP30 may be targeted for developing antiviral interventions to combat infectious diseases.
登录
查看更多内容
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
3.7
作者：
Ariumi Y;Kuroki M;Maki M;Ikeda M;Dansako H;Wakita T;Kato N
通讯作者：
Kato N
影响因子：
3.9
作者：
Harada, H;Taniguchi, T;Tanaka, N
通讯作者：
Tanaka, N
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S
影响因子：
3.5
作者：
Ehrhardt, C;Kardinal, C;Ludwig, S
通讯作者：
Ludwig, S