Ho Johnathan, Pelzel Christin, Begitt Andreas, Mee Maureen, Elsheikha Hany M, Scott David J, Vinkemeier Uwe
School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom.
PLoS Biol. 2016 Oct 25;14(10):e2000117. doi: 10.1371/journal.pbio.2000117. eCollection 2016 Oct.
STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. This, in turn, substantially attenuated cardinal IFN-γ responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein.
STAT2是I型干扰素（IFN）的典型转录因子，它与STAT1形成异二聚体发挥作用。然而，人类和小鼠STAT2缺陷型的表型表明，它还有重要的、目前尚未明确的不依赖I型干扰素的活性。在此，我们发现STAT2通过一个保守界面与STAT1组成性结合，但不与STAT3结合。虽然这种相互作用与I型干扰素信号传导及STAT1激活无关，但它特异性地阻止了STAT1在受到干扰素-γ、白细胞介素-6（IL-6）和白细胞介素-27刺激时向细胞核的转运。这是由于活化的STAT1与未磷酸化的STAT2之间发生了二聚化，由此形成的半磷酸化二聚体采取了一种无法与输入蛋白-α结合的构象。这反过来又显著减弱了主要的干扰素-γ反应，包括MHC表达、衰老和抗寄生虫免疫，并使白细胞介素-27的转录输出从STAT1转向STAT3。我们的研究结果揭示了STAT2是一种普遍存在的细胞因子调节剂，因为它在多种信号通路中抑制STAT1，并为理解该蛋白不依赖I型干扰素的活性提供了依据。
