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

• Authors: Chenyao Wang, Cleveland Clinic Foundation; Jing Nan, Lanzhou University; Elise Holvey-Bates, Cleveland Clinic Foundation; Xing Chen, Cleveland Clinic Foundation; Samantha Wightman, Cleveland Clinic Foundation; Muhammad Latif, Emory University; Junjie Zhao, Cleveland Clinic Foundation; Xiaoxia Li, Cleveland Clinic Foundation; Ganes C Sen, Cleveland Clinic Foundation; George R Stark, Cleveland Clinic Foundation; Yuxin Wang, Cleveland Clinic Foundation
• Journal Title: Proceedings of the National Academy of Sciences of the United States of America
• Volume: Volume 120, Number 16
• Publisher: PNAS. | 2023-04-18, Pages e2216953120-e2216953120
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.2216953120
• Subjects: Health Sciences, Oncology
• Keywords: DNA damage; STAT2; STING; DNA; DNA Damage; Nucleotidyltransferases; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; STAT2 Transcription Factor; Membrane Proteins

Abstract

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-κB-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.