title: The STAT3 HIES mutation is a gain-of-function mutation that activates genes via AGG-element carrying promoters.
abstract: Cytokine or growth factor activated STAT3 undergoes multiple post-translational modifications, dimerization and translocation into nuclei, where it binds to serum-inducible element (SIE, 'TTC(N3)GAA')-bearing promoters to activate transcription. The STAT3 DNA binding domain (DBD, 320-494) mutation in hyper immunoglobulin E syndrome (HIES), called the HIES mutation (R382Q, R382W or V463Δ), which elevates IgE synthesis, inhibits SIE binding activity and sensitizes genes such as TNF-α for expression. However, the mechanism by which the HIES mutation sensitizes STAT3 in gene induction remains elusive. Here, we report that STAT3 binds directly to the AGG-element with the consensus sequence 'AGG(N3)AGG'. Surprisingly, the helical N-terminal region (1-355), rather than the canonical STAT3 DBD, is responsible for AGG-element binding. The HIES mutation markedly enhances STAT3 AGG-element binding and AGG-promoter activation activity. Thus, STAT3 is a dual specificity transcription factor that promotes gene expression not only via SIE- but also AGG-promoter activity.
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Ji
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Wangping
authors.initials: W
authors.lastname: Le
authors.affiliation: Cancer Center, School of Medicine Shandong University, Culture West Street, Jinan, Shandong 250012, China.
authors.forename: Yan S
authors.initials: YS
authors.lastname: Xu
authors.affiliation: Cancer Center, School of Medicine Shandong University, Culture West Street, Jinan, Shandong 250012, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Dou
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Jieli
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Tianfei
authors.initials: T
authors.lastname: Zhong
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Dehong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Chengping
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Guan-Qun
authors.initials: GQ
authors.lastname: Xie
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai 200030,China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai 200030,China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China applezjtcm@126.com.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Fan
authors.affiliation: Department of Immune Diseases, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China yechin@sibs.ac.cn.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D006801:Humans; D007589:Job Syndrome / Q000235:genetics; D051379:Mice; D009154:Mutation; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha