Pestka S
Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
Semin Oncol. 1997 Jun;24(3 Suppl 9):S9-18-S9-40.
During the past decade, the receptors for the type I (alpha, beta, and omega) and type II (gamma) interferons (IFNs) have been identified. The IFN-gamma receptor consists of two transmembrane chains, IFN-gammaR1 and IFN-gammaR2, both of which are required for activity. The IFN-gammaR1 chain binds the IFN-gamma ligand, whereas the IFN-gammaR2 chain is required for signal transduction. After ligand binding, Jak1 and Jak2 kinases are activated by phosphorylation and then phosphorylate the IFN-gammaR1 chain, which serves as the recruitment site for Stat1alpha (signal transducers and activators of transcription). After recruitment to the phosphorylated IFN-gammaR1 chain, Stat1alpha is then phosphorylated and released to form a Stat1alpha dimer that represents the active transcription factor for IFN-gamma-induced genes. An analogous paradigm exists for the type I IFN (IFN-alpha/beta) receptor. This receptor appears to consist of two chains, IFN-alphaR1 and IFN-alphaR2, which can be present in different forms. Thus, the IFN-alphaR1 chain is present as the full chain (IFN-alphaR1a) and as a splice-variant (IFN-alphaR1s) lacking exons IV and V; the IFN-alphaR2 chain exists in soluble, short, and long forms (IFN-alphaR2a, IFN-alphaR2b, and IFN-alphaR2c, respectively). Most likely, the IFN-alphaR1a and IFN-alphaR2c chains represent the predominantly active form. After ligand binding of IFN-alpha, IFN-beta, or IFN-omega species, Tyk2 and Jak1 kinases are recruited to the receptor complex and activated. The activation results in the subsequent recruitment of Stat1 (Stat1alpha and Stat1beta) and Stat2, which form a Stat1/Stat2 heterodimer after their phosphorylation. The active transcription complex IFN-stimulated gene factor-3 is formed by the association of the Stat1/Stat2 heterodimer with the p48 protein. The active IFN-stimulated gene factor-3 binds to the promoter elements of type I IFN-induced genes to initiate their transcription. Although the overall motif appears clear, there is much complexity in these interactions in that the various type I IFNs exhibit different interactions with the receptor components. Apparently, each of the IFN-alpha species exhibits a different pattern of receptor interactions that reflects their different biologic activities and will likely explain the existence of this large family of IFN-alpha species, IFN-beta, and IFN-omega that all interact with the same basal receptor.
在过去十年中，I型（α、β和ω）和II型（γ）干扰素（IFN）的受体已被鉴定出来。IFN-γ受体由两条跨膜链组成，即IFN-γR1和IFN-γR2，二者对于活性均是必需的。IFN-γR1链结合IFN-γ配体，而IFN-γR2链对于信号转导是必需的。配体结合后，Jak1和Jak2激酶通过磷酸化被激活，然后使IFN-γR1链磷酸化，IFN-γR1链作为Stat1α（信号转导子和转录激活子）的招募位点。招募到磷酸化的IFN-γR1链后，Stat1α随后被磷酸化并释放以形成Stat1α二聚体，该二聚体代表IFN-γ诱导基因的活性转录因子。I型IFN（IFN-α/β）受体存在类似的模式。该受体似乎由两条链组成，即IFN-αR1和IFN-αR2，它们可以以不同形式存在。因此，IFN-αR1链以全长链（IFN-αR1a）和缺少外显子IV和V的剪接变体（IFN-αR1s）形式存在；IFN-αR2链以可溶性、短和长形式存在（分别为IFN-αR2a、IFN-αR2b和IFN-αR2c）。很可能，IFN-αR1a和IFN-αR2c链代表主要的活性形式。IFN-α、IFN-β或IFN-ω类配体结合后，Tyk2和Jak1激酶被招募到受体复合物并被激活。激活导致随后招募Stat1（Stat1α和Stat1β）和Stat2，它们在磷酸化后形成Stat1/Stat2异二聚体。活性转录复合物IFN刺激基因因子-3由Stat1/Stat2异二聚体与p48蛋白结合形成。活性IFN刺激基因因子-3与I型IFN诱导基因的启动子元件结合以启动它们的转录。尽管总体模式似乎清晰，但这些相互作用存在很多复杂性，因为各种I型IFN与受体成分表现出不同的相互作用。显然，每个IFN-α类都表现出不同的受体相互作用模式，这反映了它们不同的生物学活性，并且可能解释了这个与同一基础受体相互作用的IFN-α类、IFN-β和IFN-ω大家族的存在。
