USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response.
USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response.
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DOI：
10.1371/journal.pone.0022200
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Uzé G
中科院分区：
文献类型：
--
作者：
François-Newton V;Magno de Freitas Almeida G;Payelle-Brogard B;Monneron D;Pichard-Garcia L;Piehler J;Pellegrini S;Uzé G
I型干扰素（IFN）是在微生物感染时快速分泌并调节免疫应答的所有方面的细胞因子。在人类中存在15种I型IFN亚型，其中IFN α2和IFN β在临床上用于治疗不同的病理。IFN α2和IFN β在其表达和发挥特异性生物活性的效力方面是非冗余的。最近鉴定的III型IFN（3 IFN λ或IL-28/IL-29）结合不相关的细胞类型限制性受体。这两种受体复合物的下游是共享的Jak/Stat途径。已经在分子水平上描述了几种有助于关闭IFN诱导的信号传导的机制。特别是，人们早就知道I型IFN诱导脱敏状态的建立。在这项工作中，我们询问了IFN诱导的脱敏如何整合到由多种I型IFN亚型和III型IFN构建的网络中。我们表明，用I型IFN或III型IFN引发细胞会干扰细胞进一步响应所有IFN α亚型的能力。重要的是，致敏细胞的差异脱敏是因为它们保留了对IFN β的敏感性。我们发现USP 18是通过损害IFN α2功能结合位点的形成来诱导差异脱敏的必要和充分条件。我们的数据突出了IFN α和IFN β之间的新型差异，并强调了I型和III型IFN之间的串扰。这种相互作用可能有助于阐明IFN λ基因座的遗传变异，该基因座与丙型肝炎病毒的持续存在和患者对IFN α2治疗的反应有关。
Type I interferons (IFN) are cytokines that are rapidly secreted upon microbial infections and regulate all aspects of the immune response. In humans 15 type I IFN subtypes exist, of which IFN α2 and IFN β are used in the clinic for treatment of different pathologies. IFN α2 and IFN β are non redundant in their expression and in their potency to exert specific bioactivities. The more recently identified type III IFNs (3 IFN λ or IL-28/IL-29) bind an unrelated cell-type restricted receptor. Downstream of these two receptor complexes is a shared Jak/Stat pathway. Several mechanisms that contribute to the shut down of the IFN-induced signaling have been described at the molecular level. In particular, it has long been known that type I IFN induces the establishment of a desensitized state. In this work we asked how the IFN-induced desensitization integrates into the network built by the multiple type I IFN subtypes and type III IFNs. We show that priming of cells with either type I IFN or type III IFN interferes with the cell's ability to further respond to all IFN α subtypes. Importantly, primed cells are differentially desensitized in that they retain sensitivity to IFN β. We show that USP18 is necessary and sufficient to induce differential desensitization, by impairing the formation of functional binding sites for IFN α2. Our data highlight a new type of differential between IFNs α and IFN β and underline a cross-talk between type I and type III IFN. This cross-talk could shed light on the reported genetic variation in the IFN λ loci, which has been associated with persistence of hepatitis C virus and patient's response to IFN α2 therapy.
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