title: Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis.
abstract: BACKGROUND
  The involvement of mitochondrial oxidative phosphorylation (OXPHOS) in mast cell exocytosis was recently suggested by the finding that mitochondria translocate to exocytosis sites upon mast cell activation. In parallel, mitochondrial signal transducer and activator of transcription 3 (STAT3) was found to be involved in ATP production. However, the regulation of mitochondrial STAT3 function and its connection to mast cell exocytosis is unknown.
  
  
  OBJECTIVE
  We sought to explore the role played by mitochondrial STAT3 in mast cell exocytosis.
  
  
  METHODS
  Experiments were performed in vitro with human and mouse mast cells and rat basophilic leukemia (RBL) cells and in vivo in mice. OXPHOS activity was measured after immunologic activation. The expression of STAT3, extracellular signal-regulated kinase 1/2, and protein inhibitor of activated STAT3 in the mitochondria during mast cell activation was determined, as was the effect of STAT3 inhibition on OXPHOS activity and mast cell function.
  
  
  RESULTS
  Here we show that mitochondrial STAT3 is essential for immunologically mediated degranulation of human and mouse mast cells and RBL cells. Additionally, in IgE-antigen-activated RBL cells, mitochondrial STAT3 was phosphorylated on serine 727 in an extracellular signal-regulated kinase 1/2-dependent manner, which was followed by induction of OXPHOS activity. Furthermore, the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3, was found to inhibit OXPHOS activity in the mitochondria, resulting in inhibition of mast cell degranulation. Moreover, mice injected with Stattic, a STAT3 inhibitor, had a significant decrease in histamine secretion.
  
  
  CONCLUSIONS
  These results provide the first evidence of a regulatory role for mitochondrial STAT3 in mast cell functions, and therefore mitochondrial STAT3 could serve as a new target for the manipulation of allergic diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Tal Hadad
authors.initials: TH
authors.lastname: Erlich
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yagil
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Gillian
authors.initials: G
authors.lastname: Kay
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Peretz
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Helena
authors.initials: H
authors.lastname: Migalovich-Sheikhet
authors.affiliation: Department of Nuclear Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Tshori
authors.affiliation: Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Francesca
authors.initials: F
authors.lastname: Levi-Schaffer
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Electronic address: annsr@hadassah.org.il.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: ehudr@ekmd.huji.ac.il.
authors.forename: Ehud
authors.initials: E
authors.lastname: Razin
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004140:Dinitrophenols / Q000276:immunology / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics* / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000235:genetics / Q000276:immunology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D010085:Oxidative Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000276:immunology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D000941:Antigens; D003499:Cyclic S-Oxides; D004140:Dinitrophenols; D024101:Mitochondrial Proteins; C109279:Pias3 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C517409:stattic; D007073:Immunoglobulin E; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Allergy; PIAS3; STAT3; cytokines; degranulation; mast cells; mitochondria