Implication of PMLIV in both intrinsic and innate immunity.
Implication of PMLIV in both intrinsic and innate immunity.
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DOI：
10.1371/journal.ppat.1003975
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Chelbi-Alix MK
中科院分区：
文献类型：
--
作者：
El Asmi F;Maroui MA;Dutrieux J;Blondel D;Nisole S;Chelbi-Alix MK
PML/TRIM19是核小体（NBs）的组织者，参与了对多种RNA和DNA病毒的抗病毒反应。由单个PML基因通过选择性剪接产生的几种PML同种异构体，共享包含RBCC/tripartite motif的相同n端区域，但其c端序列不同。最近对所有PML亚型的研究揭示了每种亚型的特定功能。PML基因敲除使小鼠对水疱性口炎病毒（VSV）更敏感。在PML亚型（PMLI到PMLVIIb）中，只有PMLIII和PMLIV赋予VSV抗性。与抗vsv活性不依赖于IFN的PMLIII不同，PMLIV可以在两个阶段起作用：它以IFN不依赖的方式直接赋予病毒抗性，并通过更高的IRF3激活特异性地增强IFN-β的产生，从而保护未感染的细胞免受即将到来的感染。这两种活性都需要PMLIV SUMOylation。这首次证明PMLIV通过增强IFN-β合成参与先天免疫反应。IRF3的缺失进一步证明了PMLIV的双重活性，因为它取消了PMLIV诱导的IFN合成，但没有取消PMLIV诱导的病毒蛋白抑制。在机制上，PMLIV通过调节Pin1（肽基脯氨酸顺式/反式异构酶）的细胞分布，诱导其募集到两种蛋白共定位的PML NBs，从而增强IFN-β的合成。summoylated PMLIV与内源性Pin1的相互作用及其在PML NBs中的募集阻止了活化的IRF3的降解，从而增强了IRF3依赖性IFN-β的产生。虽然PMLIV的内在抗病毒活性仅针对VSV，但它对IFN-β合成的影响要广泛得多，因为它影响先天免疫途径的一个关键因素。我们的研究结果表明，除了其固有的抗vsv活性外，PMLIV还能响应不同的诱导剂积极调节IFN-β的合成，从而将PML/TRIM19添加到与固有免疫和先天免疫相关的TRIM蛋白列表中。PML被表达为7种同工异构体，从pmlli到PMLVIIb，每一种都有其c端区域赋予的特定功能。PML异构体参与多种细胞过程，包括抗病毒防御。很少有研究对所有PML亚型进行研究，以研究它们的个体抗病毒特性。我们与所有PML亚型对VSV复制的比较研究表明，只有PMLIII和PMLIV能够以不依赖ifn的方式抑制VSV病毒。重要的是，PMLIV还能够增强IRF3磷酸化，从而在响应病毒感染时产生显著的IFN-β，从而保护未感染的细胞。相反，在人细胞中特异性抑制PMLIV表达可减少病毒诱导的IRF3激活和随后的IFN-β产生。我们发现PMLIV通过在两种蛋白共定位的PML NBs中募集这种蛋白来影响Pin1的内源性分布。这阻止了活化的IRF3降解，从而增强了IFN-β的产生。在这里，我们首次表明，除了其固有的抗vsv活性外，PMLIV还涉及抗病毒先天免疫反应。因此，PML是IFN刺激的基因，其产物具有广泛的内在抗病毒活性，其中之一PMLIV也是先天免疫途径的有效调节剂。
PML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. The knockout of PML renders mice more sensitive to vesicular stomatitis virus (VSV). Here we report that among PML isoforms (PMLI to PMLVIIb), only PMLIII and PMLIV confer resistance to VSV. Unlike PMLIII, whose anti-VSV activity is IFN-independent, PMLIV can act at two stages: it confers viral resistance directly in an IFN-independent manner and also specifically enhances IFN-β production via a higher activation of IRF3, thus protecting yet uninfected cells from oncoming infection. PMLIV SUMOylation is required for both activities. This demonstrates for the first time that PMLIV is implicated in innate immune response through enhanced IFN-β synthesis. Depletion of IRF3 further demonstrates the dual activity of PMLIV, since it abrogated PMLIV-induced IFN synthesis but not PMLIV-induced inhibition of viral proteins. Mechanistically, PMLIV enhances IFN-β synthesis by regulating the cellular distribution of Pin1 (peptidyl-prolyl cis/trans isomerase), inducing its recruitment to PML NBs where both proteins colocalize. The interaction of SUMOylated PMLIV with endogenous Pin1 and its recruitment within PML NBs prevents the degradation of activated IRF3, and thus potentiates IRF3-dependent production of IFN-β. Whereas the intrinsic antiviral activity of PMLIV is specific to VSV, its effect on IFN-β synthesis is much broader, since it affects a key actor of innate immune pathways. Our results show that, in addition to its intrinsic anti-VSV activity, PMLIV positively regulates IFN-β synthesis in response to different inducers, thus adding PML/TRIM19 to the growing list of TRIM proteins implicated in both intrinsic and innate immunity. PML is expressed as seven isoforms, designated PMLI to PMLVIIb, each with specific functions conferred by their C-terminal regions. PML isoforms are implicated in several cell processes, including antiviral defense. Very few studies have been performed with all PML isoforms to investigate their individual antiviral properties. Our comparative study with all PML isoforms on VSV replication revealed that only PMLIII and PMLIV are able to inhibit this virus in an IFN-independent way. Importantly, PMLIV is also able to enhance IRF3 phosphorylation resulting in a dramatic IFN-β production in response to viral infection, thus protecting yet uninfected cells. At the opposite, the specific suppression of PMLIV expression in human cells reduced virus-induced IRF3 activation and subsequent IFN-β production. We found that PMLIV affects the endogenous distribution of Pin1, by recruiting this protein in PML NBs where both proteins colocalize. This prevents activated IRF3 degradation, thus enhancing the production of IFN-β. Here we show for the first time that, in addition to its intrinsic anti-VSV activity, PMLIV is implicated in antiviral innate immune response. Thus, PML is an IFN stimulated gene whose products have a broad intrinsic antiviral activity and one of them, PMLIV, is also a potent regulator of innate immune pathways.
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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：
5.4
作者：
El Mchichi, Bouchra;Regad, Tarik;Chelbi-Alix, Mounira K.
通讯作者：
Chelbi-Alix, Mounira K.
影响因子：
3.7
作者：
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通讯作者：
Nisole S
影响因子：
5.4
作者：
Blondel, Danielle;Kheddache, Sabrina;Chelbi-Alix, Mounira K.
通讯作者：
Chelbi-Alix, Mounira K.
影响因子：
4.8
作者：
Kamitani, T;Kito, K;Yeh, ETH
通讯作者：
Yeh, ETH