4.8 Article

STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2216953120

Keywords

STAT2; STING; DNA damage

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In cancer cells, the abnormal presence of DNA in the cytoplasm activates cGAS and STING. STAT2 inhibits the expression of IRF3-dependent genes induced by cGAMP by binding to STING and blocking its intracellular trafficking. STAT2 reshapes STING signaling by inhibiting IRF3-dependent gene induction, but not NF-xB-dependent gene induction. This noncanonical activity of STAT2 depends on the phosphorylation of threonine 404, which promotes the formation of a STAT2:STING complex that keeps STING bound to the endoplasmic reticulum (ER) and increases resistance to DNA damage.
In cancer cells, endogenous or therapy-induced DNA damage leads to the abnormal presence of DNA in the cytoplasm, which triggers the activation of cGAS (cyclic GMP-AMP synthase) and STING (stimulator of interferon genes). STAT2 suppresses the cGAMP-induced expression of IRF3-dependent genes by binding to STING, blocking its intracellular trafficking, which is essential for the full response to STING activation. STAT2 reshapes STING signaling by inhibiting the induction of IRF3-dependent, but not NF-xB-dependent genes. This noncanonical activity of STAT2 is regulated independently of its tyrosine phosphorylation but does depend on the phosphorylation of threonine 404, which promotes the formation of a STAT2:STING complex that keeps STING bound to the endoplasmic reticulum (ER) and increases resistance to DNA damage. We conclude that STAT2 is a key negative intracellular regulator of STING, a function that is quite distinct from its function as a transcription factor.

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