ZNF341 controls STAT3 expression and thereby immunocompetence

Abstract

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-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 Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding 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.

Human hyper-IgE syndrome: singular or plural?

“…While this review was being revised, we and others reported patients with AR ZNF341 deficiency, which appears to be a phenocopy of AD STAT3 deficiency. This is understandable, as ZNF341 is a transcription factor that controls the expression, activation, and activity of STAT3 [194, 195]. One can therefore use the plural when referring to HIES, not because of AR DOCK8 and PGM3 deficiency, but because of AR ZNF341 deficiency that closely mimics AD STAT3 deficiency.…”

Who regulates whom: ZNF341 is an additional player in the STAT3/T H 17 song

“…ZNF341 regulates STAT3 expression and its autoinduction during Th17 differentiation. ( B ) Key structural motifs within ZNF341 and the location of mutations in HIES patients identified by Beziat et al and Frey-Jacobs et al 1,2 .…”

“…By investigating patients from 10 families who present with symptoms resembling monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES) but lack mutations in STAT3, two groups, Beziat et al 1 , and Frey-Jacobs et al 2 , identify a novel player in the pathway that regulates Th17 differentiation, and levels of IgE. The identification of the STAT3 mutations in humans with monogenic AD-HIES 3 , has emphasized the importance of this transcription factor in regulating Th17 cells, as well as the function of these cells in human health and disease.…”

“…leukemia inhibitory factor receptor (LIFR), IL-11R, and the gp130 common subunit of the IL-6 receptor family) 4 . Other mutations in genes such as DOCK8 2 can also lead to similar symptoms as AD-HIES (e.g. hyper-IgE syndrome or HIES), although these are autosomal recessive (AR-HIES).…”

“…Enter Beziat et al and Frey-Jacobs et al, who analyzed 10 families with reported phenotypes resembling AD-HIES 1,2 . The probands from these 10 families are largely from the middle east (Israel by way of Sudan, Turkey, Iran, and Lebanon) with one Afro-Caribbean, and all carried mutations in ZNF341, a putative transcription factor containing 12 C2H2 zinc finger domains with previously unknown function.…”