<i>STAT1</i>Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis

Veerdonk, Frank L. van de; Plantinga, Theo S.; Hoischen, Alexander; Smeekens, Sanne P.; Joosten, Leo A. B.; Gilissen, Christian; Arts, Peer; Rosentul, Diana C.; Carmichael, Andrew; Graaf, Chantal A.A. Smits-van der; Kullberg, Bart Jan; Meer, J.W.M. van der; Lilić, Desa; Veltman, Joris A.; Netea, Mihai G.

doi:10.1056/nejmoa1100102

Cited by 596 publications

(461 citation statements)

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“…Mutated STAT1 sequences were created from a modified STAT1-pRc/CMV vector (kind gift from Geeta Devgan) using site-directed mutagenesis (QuikChange Lightning Site-Directed Mutagenesis Kit; Stratagene) and primers (Supporting Information Table 2) previously described to create constructs carrying A267V and R274W mutant as well as WT STAT1 [5,6].…”

Section: Generation Of Gof-stat1 Vectorsmentioning

confidence: 99%

“…As proof of principle, it was found that the candidiasis in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy who suffer with autoimmunity as a result of AIRE gene mutations was linked to autoantibodies against Th-17 cytokines (IL-17A, IL-17F, and IL-22), elegantly explaining the CMC in the context of autoimmunity [4]. However, about half of patients with isolated CMC (Online Mendelian Inheritance in Man #614162) were found to have an underlying gainof-function (GOF) STAT1 mutation [5,6], affecting the STAT1 signaling pathway not previously known to be directly involved in IL-17 production. Nevertheless, these patients have impaired in vitro Th-17 cell proliferation and IL-17 production in response to Candida stimulation [7] explaining their CMC, but the mechanisms through which the GOF-STAT1 mutation decreases STAT3-dependent production of Th-17 cytokines remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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/cMyc) 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.Correspondence: Dr. Desa Lilic e-mail: desa.lilic@ncl.ac.uk * Both authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2834-2846 Immunity to infection 2835 Keywords: Chronic mucocutaneous candidiasis (CMC) HDAC inhibitors IL-17 STAT1 gain-of-function mutation STAT3 STAT1 inhibitorsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPatients with chronic mucocutaneous candidiasis (CMC) present with recurrent or persistent infections of the skin, nails, and mucosal membranes with the fungus Candida [1]. Candida is an opportunistic yeast that does not cause disease in healthy individuals despite inhabiting bodily surfaces as it is controlled by immune mechanisms, specifically Th-17 cells and cytokines produced by them [2]. Mucosal infections with Candida species indicate an underlying T-cell deficiency, which is most often secondary to immunosuppressive and/or chemotherapy, antibiotics, biological therapies, HIV, or other permissive circumstances. However, in rare patients, these infections present as a severe syndrome coined CMC, a primary immune deficiency in which the underlying cause is a genetic mutation affecting immune pathways essential for fungal protection [3]. Research in primary immune deficiency patients with isolated CMC has documented the crucial role of the signal transducer and activator of tra...

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Section: Generation Of Gof-stat1 Vectorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…On the other hand, its gain-of-function (GOF) mutations exhibit different immunological defects. The patients suffer from persistent or recurrent infection of the skin, nails, and mucous membranes with Candida albicans, referred to as chronic mucocutaneous candidiasis (CMC) (7)(8)(9). Assigning structural changes caused by these pathogenic amino acid substitutions has shed light on the molecular mechanisms of STAT1-mediated immunodeficiencies as well as the fundamental roles of the original residue in normal STAT1 functions.…”

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confidence: 99%

“…1B), it was initially postulated that the CCD acts as a docking platform for transcription factors to cooperatively support STAT1-mediated transcription and that GOF mutations in the CCD increased their interactions (12). Recently, another mechanism of STAT1 GOF was proposed (7,9). Dephosphorylation of Tyr-701 proceeds via anti-parallel conformation of the STAT1 dimer through phospho-Tyr-701-independent interaction between the CCD and DBD (13).…”

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confidence: 99%

“…Because these mutations frequently converged on the ␣3 helix of the CCD, we generated a series of Ala mutants of this region and measured the mutant activities using our optimized luciferase reporter assay. We especially focused on one particularly frequent GOF residue, Arg-274, because it was known as a CMC hot spot (7,9) and possessed structural features distinct from the other GOF residues. Most of the GOF residues are toward the inside of four helical bundles of the CCD or occupied on the protein surface near the interface of anti-parallel dimer formation.…”

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Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

Fujiki

Hijikata

Shirai

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonGain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease. However, the molecular basis for the gain of STAT1 function remains largely unclear. Here, we investigated the structural features of STAT1 GOF residues to better understand the impact of these pathogenic mutations. We constructed STAT1 alanine mutants of the ␣3 helix residues of the coiled-coil domain, which are frequently found in CMC pathogenic mutations, and measured their transcriptional activities. Most of the identified GOF residues were located inside the coiled-coil domain stem structure or at the protein surface of the anti-parallel dimer interface. Unlike those, Arg-274 was adjacent to the DNA-binding domain. In addition, Arg-274 was found to functionally interact with Gln-441 in the DNA-binding domain. Because Gln-441 is located at the anti-parallel dimer contact site, Gln-441 reorientation by Arg-274 mutation probably impedes formation of the dimer. Further, the statistical analysis of RNA-seq data with STAT1-deficient epithelial cells and primary T cells from a CMC patient revealed that the R274Q mutation affected gene expression levels of 66 and 76 non-overlapping RefSeq genes, respectively. Because their transcription levels were only slightly modulated by wild-type STAT1, we concluded that the R274Q mutation increased transcriptional activity but did not change dramatically the repertoire of STAT1 targets. Hence, we provide a novel mechanism of STAT1 GOF triggered by a CMC pathogenic mutation.

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An 18-Year-Old Woman With Recurrent Skin, Nail, and Oral Mucosal Abnormalities

Wang

Man

2022

JAMA

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STAT1Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis

Abstract: Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

Cited by 596 publications

References 29 publications

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

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

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

An 18-Year-Old Woman With Recurrent Skin, Nail, and Oral Mucosal Abnormalities

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