STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways.
STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways.
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STAT2是一种普遍的细胞因子调节剂，由于其在多个信号传导途径中抑制了STAT1。
DOI：
10.1371/journal.pbio.2000117
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发表时间：
2016-10
期刊：
影响因子：
9.8
通讯作者：
Vinkemeier U
中科院分区：
文献类型：
--
作者：
Ho J;Pelzel C;Begitt A;Mee M;Elsheikha HM;Scott DJ;Vinkemeier U
STAT2是1型干扰素（ifn）的典型转录因子，它与STAT1作为异源二聚体起作用。然而，人类和小鼠stat2缺陷表型提示了重要的额外且目前尚未确定的1型ifn非依赖性活性。在这里，我们发现STAT2通过一个保守接口本构地与STAT1结合，而不是STAT3。虽然这种相互作用与1型干扰素信号传导和STAT1激活无关，但它排除了STAT1在响应IFN-γ、白细胞介素-6 （IL-6）和IL-27时特异性的核易位。这可以通过激活的STAT1和未磷酸化的STAT2之间的二聚化来解释，其中半磷酸化的二聚体采用无法结合输入蛋白α的构象。这反过来又大大减弱了IFN-γ的主要反应，包括MHC表达、衰老和抗寄生虫免疫，并将IL-27的转录输出从STAT1转移到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，并提供了对该蛋白的1型干扰素非依赖性活性的理解。超过四分之一个世纪以来，我们已经知道STAT1和STAT2对于典型的宿主免疫防御系统对抗病毒感染（称为1型干扰素反应）至关重要。虽然STAT1被赋予了多个额外的角色，但STAT2被认为在1型干扰素系统中仅作为STAT1的主要合作伙伴发挥作用。然而，缺乏STAT2的患者和动物表现出令人惊讶的变化，有时是微妙的表型，不能完全解释这种蛋白质的已知功能。我们的研究揭示了STAT2作用的一个全新方面，即作为STAT1的先天抑制剂在其多种生物学作用中。我们确定了STAT1抑制的分子机制，并产生了一种新的生物学工具，我们可以用它来解离STAT2对STAT1的激活和抑制作用。我们使用这个工具来证明STAT2除了抗病毒保护外还具有重要作用，例如，在调节细胞增殖和免疫细胞功能以及杀死细胞内寄生虫方面。这些发现极大地扩展了我们对STAT2生物学的认识，并有必要重新评估先天免疫和干扰素治疗使用的核心调控机制。
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. For more than a quarter century, we have known that STAT1 and STAT2 are essential for the classic host immune defense system against viral infections known as the type 1 interferon response. While STAT1 has since been assigned multiple additional roles, STAT2 is thought to function exclusively as the principal partner of STAT1 in the type 1 interferon system. However, patients and animals that are deficient in STAT2 show a surprisingly varied and sometimes subtle phenotype not fully accounted for by the known functions of this protein. Our investigations reveal an entirely novel facet of STAT2 action, namely as an innate inhibitor of STAT1 in its multiple biological roles. We identify the molecular mechanism of STAT1 inhibition and generate a novel biological tool with which we can dissociate STAT2’s activating and inhibitory effects on STAT1. We use this tool to show that STAT2 has major roles beyond antiviral protection, for example, in regulating cell proliferation and immune cell functions, as well as in killing intracellular parasites. These findings considerably expand our knowledge of STAT2 biology and necessitate a reassessment of regulatory mechanisms central to innate immunity and the therapeutic use of interferons.
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影响因子：
30.5
作者：
Hu, XY;Herrero, C;Ivashkiv, LB
通讯作者：
Ivashkiv, LB
影响因子：
20.3
作者：
Begitt, Andreas;Droescher, Mathias;Vinkemeier, Uwe
通讯作者：
Vinkemeier, Uwe
DOI：
10.1084/jem.20110958
发表时间：
2011-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu L;Okada S;Kong XF;Kreins AY;Cypowyj S;Abhyankar A;Toubiana J;Itan Y;Audry M;Nitschke P;Masson C;Toth B;Flatot J;Migaud M;Chrabieh M;Kochetkov T;Bolze A;Borghesi A;Toulon A;Hiller J;Eyerich S;Eyerich K;Gulácsy V;Chernyshova L;Chernyshov V;Bondarenko A;Grimaldo RM;Blancas-Galicia L;Beas IM;Roesler J;Magdorf K;Engelhard D;Thumerelle C;Burgel PR;Hoernes M;Drexel B;Seger R;Kusuma T;Jansson AF;Sawalle-Belohradsky J;Belohradsky B;Jouanguy E;Bustamante J;Bué M;Karin N;Wildbaum G;Bodemer C;Lortholary O;Fischer A;Blanche S;Al-Muhsen S;Reichenbach J;Kobayashi M;Rosales FE;Lozano CT;Kilic SS;Oleastro M;Etzioni A;Traidl-Hoffmann C;Renner ED;Abel L;Picard C;Maródi L;Boisson-Dupuis S;Puel A;Casanova JL
通讯作者：
Casanova JL
影响因子：
11.4
作者：
Cheon, HyeonJoo;Holvey-Bates, Elise G.;Schoggins, John W.;Forster, Samuel;Hertzog, Paul;Imanaka, Naoko;Rice, Charles M.;Jackson, Mark W.;Junk, Damian J.;Stark, George R.
通讯作者：
Stark, George R.
DOI：
10.1073/pnas.89.16.7840
发表时间：
1992-08-15
影响因子：
11.1
作者：
FU, XY;SCHINDLER, C;DARNELL, JE
通讯作者：
DARNELL, JE