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STAT2 hinders STING intracellular trafficking and reshapes its activation in response 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 bindi...

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Autores principales: Wang, Chenyao, Nan, Jing, Holvey-Bates, Elise, Chen, Xing, Wightman, Samantha, Latif, Muhammad-Bilal, Zhao, Junjie, Li, Xiaoxia, Sen, Ganes C., Stark, George R., Wang, Yuxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120020/
https://www.ncbi.nlm.nih.gov/pubmed/37036972
http://dx.doi.org/10.1073/pnas.2216953120
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author Wang, Chenyao
Nan, Jing
Holvey-Bates, Elise
Chen, Xing
Wightman, Samantha
Latif, Muhammad-Bilal
Zhao, Junjie
Li, Xiaoxia
Sen, Ganes C.
Stark, George R.
Wang, Yuxin
author_facet Wang, Chenyao
Nan, Jing
Holvey-Bates, Elise
Chen, Xing
Wightman, Samantha
Latif, Muhammad-Bilal
Zhao, Junjie
Li, Xiaoxia
Sen, Ganes C.
Stark, George R.
Wang, Yuxin
author_sort Wang, Chenyao
collection PubMed
description 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.
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spelling pubmed-101200202023-04-22 STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage Wang, Chenyao Nan, Jing Holvey-Bates, Elise Chen, Xing Wightman, Samantha Latif, Muhammad-Bilal Zhao, Junjie Li, Xiaoxia Sen, Ganes C. Stark, George R. Wang, Yuxin Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-04-10 2023-04-18 /pmc/articles/PMC10120020/ /pubmed/37036972 http://dx.doi.org/10.1073/pnas.2216953120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Wang, Chenyao
Nan, Jing
Holvey-Bates, Elise
Chen, Xing
Wightman, Samantha
Latif, Muhammad-Bilal
Zhao, Junjie
Li, Xiaoxia
Sen, Ganes C.
Stark, George R.
Wang, Yuxin
STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title_full STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title_fullStr STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title_full_unstemmed STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title_short STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage
title_sort stat2 hinders sting intracellular trafficking and reshapes its activation in response to dna damage
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120020/
https://www.ncbi.nlm.nih.gov/pubmed/37036972
http://dx.doi.org/10.1073/pnas.2216953120
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