Ahmed Chulbul M, Johnson Howard M
Department of Microbiology and Cell Science; University of Florida; Gainesville, FL USA.
JAKSTAT. 2013 Oct 1;2(4):e26227. doi: 10.4161/jkst.26227. Epub 2013 Sep 4.
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.
细胞因子如干扰素（IFN）的信号传导涉及Janus激酶（JAK）和信号转导及转录激活因子（STAT）转录因子。JAK-STAT信号传导经典模型的美妙之处在于其简单性，即细胞核中JAK激活的STAT负责特定基因的激活。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、组织和器官水平发挥不同功能，这一事实表明经典模型存在重大缺陷。我们的研究促成了一种非经典的、更复杂的IFN信号传导模型的发展，该模型与类固醇激素（SH）/类固醇受体（SR）信号传导模型惊人地相似。因此，I型和II型IFN信号传导都涉及复合配体、受体、激活的JAK和激活的STAT向IFN特异性激活的基因启动子的核转位，在那里它们参与特定基因的激活和表观遗传重塑。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非细胞内结合。此外，I型IFN模拟物为实验性自身免疫性脑脊髓炎（EAE，一种多发性硬化症模型）提供治疗保护，且无副作用。完整IFN与细胞外受体结合是出现流感样症状、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为这种信号传导的特异性以及IFN模拟物的开发机制提供了见解。我们认为该模型适用于其他细胞因子。
