Volume 31, No 2, Feb 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 2, February 2021: 206-218   |  Open Access

ORIGINAL ARTICLES

A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses

Yuxin Wang¹ , Qiaoling Song² , Wei Huang³ , Yuxi Lin⁴ , Xin Wang⁵ , Chenyao Wang⁶ , Belinda Willard⁷ , Chenyang Zhao⁵ , Jing Nan⁴ , Elise Holvey-Bates¹ , Zhuoya Wang² , Derek Taylor³ , Jinbo Yang^2,* , George R. Stark^1,*

¹Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
²Marine Drug Screening and Evaluation Platform, Qingdao National Laboratory for Marine Science and Technology, Ocean University of China, Qingdao, Shandong 266071, China
³Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
⁴Institute of Cancer Biology and Drug Screening, School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
⁵Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao, Shandong 266071, China
⁶Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
⁷Proteomics and Metabolomics Laboratory, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Correspondence: Jinbo Yang(yangjb@ouc.edu.cn)George R. Stark(starkg@ccf.org)

Type I interferons (IFN-I) protect us from viral infections. Signal transducer and activator of transcription 2 (STAT2) is a key component of interferon-stimulated gene factor 3 (ISGF3), which drives gene expression in response to IFN-I. Using electron microscopy, we found that, in naive cells, U-STAT2, lacking the activating tyrosine phosphorylation, forms a heterodimer with U-STAT1 in an inactive, anti-parallel conformation. A novel phosphorylation of STAT2 on T404 promotes IFN-I signaling by disrupting the U-STAT1-U-STAT2 dimer, facilitating the tyrosine phosphorylation of STATs 1 and 2 and enhancing the DNA-binding ability of ISGF3. IKK-ε, activated by virus infection, phosphorylates T404 directly. Mice with a T-A mutation at the corresponding residue (T403) are highly susceptible to virus infections. We conclude that T404 phosphorylation drives a critical conformational switch that, by boosting the response to IFN-I in infected cells, enables a swift and efficient antiviral defense.

https://doi.org/10.1038/s41422-020-0386-6

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