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Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

Jie Zheng1, Frank L van de Veerdonk2, Katherine L Crossland1

  • 1Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

European Journal of Immunology
|August 11, 2015
PubMed

Insights

Gain-of-function STAT1 mutations impair Signal transducer and activator of transcription 3 (STAT3) gene transcription, reducing protective Th-17 cytokines in chronic mucocutaneous candidiasis. This defect is reversible via epigenetic modification, suggesting new therapeutic avenues.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Signal transducer and activator of transcription 3 (STAT3) and Th-17 cytokines are crucial for fungal immunity.
  • Chronic mucocutaneous candidiasis (CMC) is linked to impaired STAT3/interleukin 17 (IL-17) pathways.
  • Gain-of-function (GOF) STAT1 mutations in autosomal dominant CMC cause defective Th17 responses, but their effect on STAT3 is not fully understood.

Purpose of the Study:

  • To investigate how GOF-STAT1 mutations impact STAT3 activation, DNA binding, gene expression, and epigenetic modifications.
  • To elucidate the mechanism behind decreased IL-17 production in CMC patients with GOF-STAT1 mutations.

Main Methods:

  • Assessed STAT3 phosphorylation, nuclear translocation, and STAT1/STAT3 heterodimer formation.
  • Analyzed STAT3-inducible gene transcription, STAT DNA binding affinity, and cytokine production.
  • Utilized histone deacetylase (HDAC) inhibitors (trichostatin A, ITF2357) and HDAC1/2/3 silencing to evaluate epigenetic modifications.

Main Results:

  • Impaired STAT3 phosphorylation, nuclear translocation, or STAT1/STAT3 heterodimerization were ruled out.
  • Significantly reduced transcription of STAT3-inducible genes (e.g., RORC, IL-17, IL-22) was observed.
  • STAT3 binding to an endogenous DNA target was impaired, while binding to high-affinity elements remained intact.
  • Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 or enhancing histone acetylation using HDAC inhibitors.
  • HDAC1 and HDAC2 were implicated in the observed epigenetic dysregulation.

Conclusions:

  • Reduced STAT3-dependent gene transcription is the underlying mechanism for diminished Th-17 responses in GOF-STAT1 CMC.
  • Epigenetic modifications, specifically histone acetylation, play a critical role in regulating STAT3 function in this context.
  • Targeting epigenetic pathways, particularly HDACs, offers a promising therapeutic strategy for CMC.
Keywords:
Chronic mucocutaneous candidiasis (CMC) ⋅ HDAC inhibitors ⋅ IL-17 ⋅ STAT1 gain-of-function mutation ⋅ STAT3 ⋅ STAT1 inhibitors

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