title: Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC).
abstract: Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant 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. We also 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.
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Crossland
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.affiliation: Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Chun M
authors.initials: CM
authors.lastname: Chan
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Al Shehri
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.affiliation: Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Lendrem
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
authors.affiliation: Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Regional Immunology and Allergy Department, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Desa
authors.initials: D
authors.lastname: Lilic
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C012589:trichostatin A; D006655:Histone Deacetylases; C502418:givinostat hydrochloride
keywords: Chronic mucocutaneous candidiasis (CMC) ⋅ HDAC inhibitors ⋅ IL-17 ⋅ STAT1 gain-of-function mutation ⋅ STAT3 ⋅ STAT1 inhibitors