The role of a non-canonical JAK-STAT pathway in IFN therapy of poxvirus infection and multiple sclerosis: An example of Occam's Broom?
The role of a non-canonical JAK-STAT pathway in IFN therapy of poxvirus infection and multiple sclerosis: An example of Occam's Broom?
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DOI：
10.4161/jkst.26227
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发表时间：
2013-10-01
期刊：
影响因子：
--
通讯作者：
Johnson HM
中科院分区：
文献类型：
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作者：
Ahmed CM;Johnson HM
细胞因子如干扰素（IFN）的信号传导涉及Janus激酶（JAK）和信号转导和转录激活因子（STAT）转录因子。JAK-STAT信号传导的经典模型的美妙之处在于它的简单性，因为细胞核中的JAK激活的STAT负责特定的基因激活。许多配体、生长因子和激素使用相同的STAT转录因子，但在细胞、组织和器官水平上发挥不同的功能，这一事实表明经典模型存在显著缺陷。我们的研究已经导致了一个非典型的，更复杂的模型IFN信号，具有惊人的相似之处，类固醇激素（SH）/类固醇受体（SR）信号的发展。因此，I型和II型IFN信号传导均涉及复合的配体、受体、活化的JAK和活化的STAT的核转位至由IFN特异性活化的基因的启动子，其中它们参与特异性基因活化和表观遗传重塑。受体胞内结构域在结合IFN的C-末端中起重要作用，这是我们开发IFN模拟物的基础。IFN模拟物不被痘病毒诱饵受体识别，因为诱饵受体竞争细胞外结合而不是细胞内结合。此外，I型IFN模拟物提供针对实验性过敏性脑脊髓炎（EAE）（多发性硬化症的模型）的治疗性保护，而没有副作用。细胞外受体与完整IFN的结合是流感样症状、骨髓抑制和体重减轻等不良副作用的主要原因。因此，IFN信号传导的非经典模型提供了对这种信号传导的特异性和开发IFN模拟物的机制的深入了解。我们的论点是，该模型适用于其他细胞因子。
Signaling by cytokines such as the interferons (IFNs) involves Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. The beauty of the classical model of JAK-STAT signaling is its simplicity in that JAK-activated STATs in the nucleus are responsible for specific gene activation. The fact that many ligands, growth factors, and hormones use the same STAT transcription factors, but exert different functions at the level of the cell, tissue, and organ would suggest significant shortcomings in the classical model. Our studies have resulted in the development of a non-canonical, more complex model of IFN signaling that bears a striking resemblance to that of steroid hormone (SH)/steroid receptor (SR) signaling. Thus, both types I and II IFN signaling involves nuclear translocation of complexed ligand, receptor, activated JAKs, and activated STATs to the promoters of the genes that are specifically activated by the IFNs, where they are involved in specific gene activation and epigenetic remodeling. Receptor intracellular domains play an important role in binding the C-terminus of the IFNs, which is the basis for our development of IFN mimetics. The IFN mimetics are not recognized by poxvirus decoy receptors, since the decoy receptors compete for extracellular binding and not intracellular binding. Further, the type I IFN mimetics provide therapeutic protection against experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, without the side effects. Extracellular receptor binding by intact IFN is the primary reason for undesirable side effects of flu-like symptoms, bone-marrow suppression, and weight loss. The non-canonical model of IFN signaling thus provides insight into the specificity of such signaling and a mechanism for development of IFN mimetics. It is our contention that this model applies to other cytokines.