Journal
CELL RESEARCH
Volume 31, Issue 2, Pages 206-218Publisher
SPRINGERNATURE
DOI: 10.1038/s41422-020-0386-6
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Funding
- National Institutes of Health [PO1 CA062220]
- National Natural Science Foundation of China [31700751, 31571439]
- AoShan Talents Program of Qingdao National Laboratory for Marine Science and Technology [2017ASTCP-OS11]
- Qingdao Innovation Leading Talent project [16-83-11-zhc]
- U.S. Department of Education school improvement grant [S10OD023436]
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Type I interferons (IFN-I) play a crucial role in protecting against viral infections, with STAT2 being a key component in driving gene expression in response to IFN-I. The phosphorylation of STAT2 at T404 acts as a critical conformational switch, disrupting an inactive STAT1-STAT2 dimer and enhancing the antiviral defense response to IFN-I. Additionally, virus infection-induced activation of IKK-epsilon can directly phosphorylate T404, further facilitating the antiviral defense mechanism.
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-epsilon, 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.
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