NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication.
NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication.
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DOI：
10.4049/jimmunol.1000114
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发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Beg AA
中科院分区：
文献类型：
--
作者：
Wang J;Basagoudanavar SH;Wang X;Hopewell E;Albrecht R;García-Sastre A;Balachandran S;Beg AA
RNA病毒感染导致1型干扰素（IFN）的表达，特别是IFN-α/β，其在宿主抗病毒应答中起关键作用。1型IFN通过Toll样受体和RIG-I样受体途径以细胞类型特异性方式诱导，这两种途径均激活干扰素调节因子（IRF）和核因子κB（NF-κB）转录因子。虽然RNA病毒感染后NF-κB的活化和与IFN-β启动子的结合已被充分证明，但我们以前的工作令人惊讶地表明，NF-κB对IFN-β基因表达不是必需的。因此，NF-κB在IFN-β表达和病毒复制中的实际功能尚不清楚。在本研究中，我们发现NDV和VSV在缺乏NF-κB RelA亚单位的小鼠胚胎成纤维细胞（MEFs）中的复制增强。病毒复制增加可追溯到早期病毒诱导的IFN-β表达中对RelA的特定需求。在这些时间点，当IFN-β表达低于峰值水平约100倍时，受损的IFN-β产生延迟IFN诱导的基因表达，导致RelA−/− MEFs中病毒复制增加。重要的是，我们的研究结果表明，RelA的要求是至关重要的，只有当IRF 3激活低。因此，高水平的活化IRF 3表达足以诱导RelA−/− MEFs中的IFN-β，与共激活因子CREB结合蛋白（CBP）的转录协同作用，以及拯救对病毒的易感性。总之，这些发现表明NF-κB RelA对于调节总体IFN-β产生并不像以前认为的那样至关重要;相反，RelA仅在病毒感染后的关键早期阶段是特别需要的，这实质上影响了宿主对病毒感染的反应。
RNA virus infection results in expression of type 1 interferons (IFNs), especially IFN-α/β, which play a crucial role in host anti-virus responses. Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor κB (NF-κB) transcription factors. While NF-κB activation and association with the IFN-β promoter after RNA virus infection is well documented, our previous work showed that, surprisingly, NF-κB is not essential for IFN-β gene expression. Thus, the actual function of NF-κB in IFN-β expression and virus replication is not clear. In this study, we found NDV and VSV replication is enhanced in mouse embryonic fibroblasts (MEFs) lacking the NF-κB RelA subunit. Increased virus replication was traced to a specific requirement for RelA in early virus-induced IFN-β expression. At these time points, when IFN-β expression is ~100-fold less than peak levels, impaired IFN-β production delayed IFN-induced gene expression, resulting in increased virus replication in RelA−/− MEFs. Importantly, our results show that RelA requirement is crucial only when IRF3 activation is low. Thus, high levels of activated IRF3 expression are sufficient for induction of IFN-β in RelA−/− MEFs, transcriptional synergism with the coactivator CREB-binding protein (CBP), and rescue of susceptibility to virus. Together, these findings indicate that NF-κB RelA is not crucial for regulating overall IFN-β production as previously believed; instead, RelA is specifically required only during a key early phase after virus infection, which substantially impacts the host response to virus infection.
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