ZNF341 controls STAT3 expression and thereby immunocompetence.
Stefanie Frey-JakobsJulia M HartbergerManfred FliegaufClaudia BossenMagdalena L WehmeyerJohanna C NeubauerAlla BulashevskaMichele ProiettiPhilipp FröbelChristina NöltnerLinlin YangJessica Rojas-RestrepoNiko LangerSandra WinzerKarin R EngelhardtCristina GlockerDietmar PfeiferAdi KleinAlejandro A SchäfferIrina LagovskyIdit Lachover-RothVivien BéziatAnne PuelJean Laurent CasanovaBernhard FleckensteinStephan WeidingerSara Sebnem KilicBen-Zion GartyAmos EtzioniBodo GrimbacherPublished in: Science immunology (2019)
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
Keyphrases
- transcription factor
- cell proliferation
- end stage renal disease
- ejection fraction
- chronic kidney disease
- poor prognosis
- wild type
- gene expression
- prognostic factors
- stem cells
- high resolution
- peritoneal dialysis
- dna methylation
- bone marrow
- binding protein
- physical activity
- mesenchymal stem cells
- sleep quality
- dna binding