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Gain-of-function STAT1 mutations impair STAT3 activity in patients with Chronic Mucocutaneous Candidiasis (CMC)

Lookup NU author(s): Dr Katherine Crossland, Dr Chun Chan, Tariq AlShehri, Dr Mario Abinun, Professor Andrew GenneryORCiD, Professor Jelena Mann, Dr Dennis LendremORCiD, Emeritus Professor Drew Rowan, Dr Desa Lilic

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Abstract

Signal transducer and activator of transcription 3 (STAT3)-triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/IL-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/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-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.

Publication metadata

Author(s): Zheng J, vandeVeerdonk FL, Crossland KL, Smeekens SP, Chan CM, AlShehri T, Abinun M, Gennery AR, Mann J, Lendrem DW, Netea MG, Rowan AD, Lilic D

Publication type: Article

Publication status: Published

Journal: European Journal of Immunology

Year: 2015

Volume: 45

Issue: 10

Pages: 2834-2846

Print publication date: 01/10/2015

Online publication date: 01/09/2015

Acceptance date: 31/07/2015

ISSN (print): 0014-2980

ISSN (electronic): 1521-4141

Publisher: Wiley V C H Verlag GmbH & Co. KGaA

URL: http://dx.doi.org/10.1002/eji.201445344

DOI: 10.1002/eji.201445344

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