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Mitochondrial STAT3 plays a major role in IgE-antigen–mediated mast cell exocytosis - 01/08/14

Doi : 10.1016/j.jaci.2013.12.1075 
Tal Hadad Erlich, MSc a, , Zohar Yagil, PhD a, , Gillian Kay, PhD a, Alona Peretz a, Helena Migalovich-Sheikhet, PhD b, Sagi Tshori, MD, PhD c, Hovav Nechushtan, MD, PhD d, Francesca Levi-Schaffer, PharmD, PhD b, , Ann Saada, PhD e, , Ehud Razin, PhD a,
a Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel 
b Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel 
c Department of Nuclear Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel 
d Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel 
e Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel 

Corresponding author: Ehud Razin, PhD, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, POB 12272, Jerusalem 91120, Israel.Ann Saada, PhD, Monique and Jacques Roboh Department of Genetic Research, and the Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, POB 1200, 91120 Jerusalem, Israel.

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.

Conclusion

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.

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Key words : Allergy, mast cells, degranulation, cytokines, PIAS3, STAT3, mitochondria

Abbreviations used : BMMC, CBMC, DMSO, DNP, ERK1/2, OXPHOS, PIAS3, RBL, SDH, siRNA, STAT3


Plan


 Supported by the United States Binational Science Foundation (to E.R.), the Israeli Academy of Science (to E.R.), The German-Israel Foundation for Scientific Research and Development (to E.R.), the National Research Foundation of Singapore (HUJ-CREATE; to E.R.), and the Morasha Foundation Fund (to H.N.). Z.Y. was supported by the Canadian Friends of Hebrew University.
 Disclosure of potential conflict of interest: T. H. Erlich, Z. Yagil, G. Kay, A. Peretz, H. Migalovich-Sheikhet, S. Tshori, and E. Razin have received research support from the Israeli Academy of Science, BSF, NRF, and GIF. H. Nechushtan has received research support from the Morasha Foundation Fund. F. Levi-Schaffer has received research support from the Israeli Ministry of Industrial Trade and is a board member for the Israeli Ministry of Health. A. Saada declares that she has no relevant conflicts of interest.


© 2014  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 134 - N° 2

P. 460 - août 2014 Retour au numéro
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