Gain-of-function human <i>STAT1</i> mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Liu, Luyan; Okada, Satoshi; Kong, Xiao‐Fei; Kreins, Alexandra; Cypowyj, Sophie; Abhyankar, Avinash; Toubiana, Julie; Itan, Yuval; Audry, Magali; Nitschké, Patrick; Masson, Cécile; Töth, Beáta; Flatot, Jérome; Migaud, Mélanie; Chrabieh, Maya; Kochetkov, Tatiana; Bolze, Alexandre; Borghesi, A.; Toulon, A.; Hiller, Julia; Eyerich, Stefanie; Eyerich, Kilian; Gulácsy, Vera; Chernyshova, Ludmyla; Chernyshov, Viktor P.; Бондаренко, Анастасія; Grimaldo, Rosa María Cortés; Blancas-Galicia, Lizbeth; Beas, Ileana Maria Madrigal; Roesler, Joachim; Magdorf, K.; Engelhard, Dan; Thumerelle, C.; Burgel, Pierre‐Régis; Hoernes, Miriam; Drexel, Barbara; Seger, Reinhard; Kusuma, Theresia; Jansson, Annette; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H.; Jouanguy, Emmanuelle; Bustamante, Jacinta; Bué, Mélanie; Karin, Nathan; Wildbaum, Gizi; Bodemer, Christine; Lortholary, Olivier; Fischer, Alain; Blanche, Stéphane; Al‐Muhsen, Saleh; Reichenbach, Janine; Kobayashi, Masao; Espinosa-Rosales, Francisco; Lozano, Carlos Torres; Kılıç, Sara Şebnem; Oleastro, Matías; Etzioni, Amos; Traidl‐Hoffmann, Claudia; Renner, Ellen D.; Abel, Laurent; Pïcard, Capucine; Maródi, László; Boisson–Dupuis, Stéphanie; Puel, Anne; Casanova, Jean‐Laurent

doi:10.1084/jem.20110958

Cited by 713 publications

(700 citation statements)

References 70 publications

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“…Gln-275, Lys-278, Glu-282, and Lys-286) appeared to form the protein surface. As shown in previous reports, these results supported the hypothesis that two structurally distinct mechanisms were involved in the gain of STAT1 function that was associated with CMC pathogenesis (7). However, in a structural aspect, Arg-274 appeared unique because it possessed both of these structural properties.…”

Section: Implication Of Three Distinct Structural Disorders Of Stat1 supporting

confidence: 89%

“…3C). Together, these data supported the idea that mutation of Arg-274 influenced a regulatory mechanism of Tyr-701 phosphorylation (7).…”

Section: Influence Of R274q Mutations On the Regulation Of Tyr-701 Phsupporting

confidence: 77%

“…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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confidence: 99%

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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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Section: Implication Of Three Distinct Structural Disorders Of Stat1 supporting

confidence: 89%

“…3C). Together, these data supported the idea that mutation of Arg-274 influenced a regulatory mechanism of Tyr-701 phosphorylation (7).…”

Section: Influence Of R274q Mutations On the Regulation Of Tyr-701 Phsupporting

confidence: 77%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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The Skin and Disorders of the Haematopoietic and Immune Systems

Gniadecki

2016

Rook's Textbook of Dermatology, Ninth Edition

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This chapter reviews skin diseases and symptoms that develop secondarily to underlying malignant or benign diseases of the haematopoietic system. Skin lesions may be caused directly by infiltration of the skin with malignant cells (leukaemia cutis and lymphomatous infiltrates) or by paraproteins secreted by malignant plasma cells (amyloid light‐chain amyloidosis, type I cryoglobulinaemia and macroglobulinaemia cutis). A number of skin signs are an indirect effect of the underlying malignancy, such as paraneoplastic conditions or dermatological syndromes associated with haematological neoplasms (Schnitzler syndrome, POEMS, AESOP and TEMPI syndromes, neurofibromatosis, juvenile xanthogranuloma and juvenile myeloid leukaemia). Kikuchi–Fujimoto disease, Kimura disease, Rosai–Dorfman disease and IgG4‐related disease are idiopathic lymphoadenopathies presenting with characteristic skin lesions. Skin infections, eczematous lesions and vasculitis are the most common cutaneous signs of an underlying immunodeficiency. Chronic skin ulcers may accompany different haemoglobinopathies, such as thalassaemias and sickle cell anaemia. Finally, the skin signs of transfusion reactions (acute allergic reactions, transfusion‐associated graft‐versus‐host disease and post‐transfusion purpura) are reviewed. Diseases of the haematopoietic system often manifest themselves in the skin, and some manifestations are so typical that the dermatologist may be the first physician to detect the underlying blood disorder. More commonly, however, skin symptoms arise in the context of a known haematopoietic disease.

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Chronic Infections of the Small Intestine

Bourke¹,

Hussey²

2015

Yamada' S Textbook of Gastroenterology

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Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Abstract: Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease.

Cited by 713 publications

References 70 publications

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

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

The Skin and Disorders of the Haematopoietic and Immune Systems

Chronic Infections of the Small Intestine

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