PML Body Component Sp100A Is a Cytosolic Responder to IFN and Activator of Antiviral ISGs.
PML Body Component Sp100A Is a Cytosolic Responder to IFN and Activator of Antiviral ISGs.
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PML 身体成分 Sp100A 是 IFN 的细胞溶质应答剂和抗病毒 ISG 的激活剂
作者：
PML小体位于各种重要生物学过程的中心;然而，这些大分子蛋白质复合物的信号转导网络仍然是个谜。本研究说明，在详细的和第一次，信号接收，处理和实施的过程中，由PML机构在IFN和病毒感染。摘要早幼粒细胞白血病蛋白（PML）体参与干扰素（IFN）诱导抗病毒状态的关键途径之一，但其相互作用的分子机制尚不清楚。在此，我们报道了PML体的主要组成成分Sp100 A，普遍存在于各种细胞类型的胞质溶胶中，并且是多种细胞外刺激的即时反应者，包括病毒感染、IFN、表皮生长因子（EGF）、胶质细胞源性神经因子（GDNF）等，通过磷脂酰肌醇3-激酶（PI 3 K）途径进行信号传导。IFN-β诱导Sp100 A在Ser 188上的磷酸化，这加强了Sp100 A与丙酮酸激酶2（PKM 2）的结合，并促进其通过细胞外信号调节激酶1/2（ERK 1/2）-PKM 2-PIN 1-importin轴的核输入。阻断PI 3 K通路信号或干扰ERK 1/2-PKM 2-PIN 1-importin轴独立地阻碍了Sp100 A响应IFN的核转位，反映了控制该事件的双重调节机制。在细胞核中，Sp100 A富集在必需的抗病毒干扰素刺激基因（ISG）（例如编码IFI 16、OAS 2和RIG-I的基因）的启动子区，并激活它们的转录。重要的是，Sp100 A的核输入，而不是积累的突变体Sp100 A，未能响应IFN，在感染期间，有力地增强这些抗病毒ISG的转录和限制病毒繁殖。这些研究结果描绘了一种新的干扰素反应机制的PML机构在胞质溶胶和揭示复杂的传感调节网络的PML机构。重要性PML体位于各种重要生物学过程的中心;然而，这些大分子蛋白质复合物的信号转导网络仍然是个谜。本研究说明，在详细的和第一次，信号接收，处理和实施的过程中，由PML机构在IFN和病毒感染。这表明PML体组成成分Sp100 A在Ser 188上被IFN信号转导通过胞质溶胶中的PI 3 K途径磷酸化，与PKM 2共易位到细胞核中，富集在必需的抗病毒ISG（例如编码IFI 16、RIG-I、OAS 2等的ISG）的启动子区域上，并介导它们的转录激活。
PML bodies sit at the center stage of various important biological processes; however, the signal transduction networks of these macromolecular protein complexes remain enigmatic. The present study illustrates, in detail and for the first time, the course of signal receiving, processing, and implementation by PML bodies in response to IFN and virus infection. ABSTRACT Promyelocytic leukemia protein (PML) bodies are implicated in one of the key pathways in the establishment of antiviral status in response to interferon (IFN), yet the molecular mechanisms bridging the cross talk remain elusive. Herein, we report that a major constitutive component of the PML body, Sp100A, is ubiquitously located in the cytosol of various cell types and is an immediate responder to multiple extracellular stimuli, including virus infection, IFN, epidermal growth factor (EGF), glial cell-derived nerve factor (GDNF), etc., signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. IFN-β induces phosphorylation of Sp100A on Ser188, which fortifies the binding of Sp100A to pyruvate kinase 2 (PKM2) and facilitates its nuclear importation through the extracellular signal-regulated kinase 1/2 (ERK1/2)-PKM2-PIN1-importin axes. Blocking PI3K pathway signaling or interference with the ERK1/2-PKM2-PIN1-importin axes independently hampers nuclear translocation of Sp100A in response to IFN, reflecting a dual-regulation mechanism governing this event. In the nucleus, Sp100A is enriched in the promoter regions of essential antiviral interferon-stimulated genes (ISGs), such as those coding for IFI16, OAS2, and RIG-I, and activates their transcription. Importantly, nuclear importation of Sp100A, but not accumulation of a mutant Sp100A that failed to respond to IFN, during infection potently enhanced transcription of these antiviral ISGs and restricted virus propagation. These findings depict a novel IFN response mechanism by PML bodies in the cytosol and shed light on the complex sensing-regulatory network of PML bodies. IMPORTANCE PML bodies sit at the center stage of various important biological processes; however, the signal transduction networks of these macromolecular protein complexes remain enigmatic. The present study illustrates, in detail and for the first time, the course of signal receiving, processing, and implementation by PML bodies in response to IFN and virus infection. It shows that PML body constitutive component Sp100A was phosphorylated on Ser188 by IFN signaling through the PI3K pathway in the cytosol, cotranslocated into the nucleus with PKM2, enriched on the promoter regions of essential antiviral ISGs such as those coding for IFI16, RIG-I, OAS2, etc., and mediating their transcriptional activation.
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影响因子：
5.7
作者：
Collados Rodríguez M
通讯作者：
Collados Rodríguez M
影响因子：
5.4
作者：
Chelbi-Alix, MK;Quignon, F;De Thé, H
通讯作者：
De Thé, H
影响因子：
8
作者：
Carbone, R;Pearson, M;Pelicci, PG
通讯作者：
Pelicci, PG
DOI：
10.1073/pnas.92.10.4477
发表时间：
1995-05-09
影响因子：
11.1
作者：
LAWSON, ND;STILLMAN, EA;ROSE, JK
通讯作者：
ROSE, JK
影响因子：
5.4
作者：
Blondel, Danielle;Kheddache, Sabrina;Chelbi-Alix, Mounira K.
通讯作者：
Chelbi-Alix, Mounira K.