Title |
Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)
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Published in |
European Journal of Immunology, September 2015
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DOI | 10.1002/eji.201445344 |
Pubmed ID | |
Authors |
Jie Zheng, Frank L van de Veerdonk, Katherine L Crossland, Sanne P Smeekens, Chun M Chan, Tariq Al Shehri, Mario Abinun, Andrew R Gennery, Jelena Mann, Dennis W Lendrem, Mihai G Netea, Andrew D Rowan, Desa Lilic |
Abstract |
Signal transducer and activator of transcription 3 (STAT3)-triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/STAT3-17 pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of Chronic Mucocutaneous Candidiasis (CMC). In patients with autosomal-dominant (AD)-CMC we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. In patients with AD-CMC, we assessed how GOF-STAT1 mutations affect STAT3 activation, DNA-binding, gene expression, cytokine production and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation and sequestration of STAT3 into STAT1/STAT1 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/RORC-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2 and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC which can be reversed by inhibiting acetylation, offering novel targets for future therapies. This article is protected by copyright. All rights reserved. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 2 | 50% |
France | 1 | 25% |
Unknown | 1 | 25% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 4 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Netherlands | 1 | 1% |
Argentina | 1 | 1% |
Unknown | 97 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 17 | 17% |
Student > Master | 12 | 12% |
Student > Bachelor | 10 | 10% |
Other | 10 | 10% |
Researcher | 8 | 8% |
Other | 13 | 13% |
Unknown | 29 | 29% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 18 | 18% |
Agricultural and Biological Sciences | 16 | 16% |
Biochemistry, Genetics and Molecular Biology | 14 | 14% |
Immunology and Microbiology | 14 | 14% |
Nursing and Health Professions | 1 | 1% |
Other | 2 | 2% |
Unknown | 34 | 34% |