STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: A novel mutation

Halaçlı, Sevil Oskay; Çağdaş, Deniz; Sun-Tan, Cağman; Erman, Baran; Uz, Elif; Yılmaz, Didem; Ozgul, Koksal; Tezcan, İlhan; Sanal, Özden

doi:10.1016/j.clim.2015.06.010

Cited by 77 publications

(53 citation statements)

References 15 publications

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“…Instead, DOCK8 acted as an adaptor and negatively regulated nuclear translocation of EPAS1 through the interaction with MST1. Interestingly, it has been reported that 7 of 9 patients with MST1 mutations had eczema or AD-like skin disease464748, raising the possibility that MST1 is also involved in IL-31 induction. Indeed, we found that Il31 gene expression markedly increased in CD4 + T cells when Mst1 gene was knocked down.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

et al. 2017

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Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

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Section: Discussionmentioning

confidence: 99%

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

et al. 2017

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“…For example, an increased apoptosis and inflammation by depletion of Mst1 has been observed in some systems (Thompson and Sahai 2015). Loss of Mst1 also renders mice predisposed to autoimmune disorders Fukuhara et al 2015;Halacli et al 2015;Thompson and Sahai 2015). Furthermore, SNPs in Mst1 are associated with both Crohn's disease and colitis (Waterman et al 2011;Nimmo et al 2012).…”

Section: Function Of Mst1 In Host Antiviral Defense and Beyondmentioning

confidence: 99%

“…LC3, one of the main players in autophagy, was also recently identified as a substrate of Mst1/2 (Wilkinson and Hansen 2015). Most intriguingly, loss of Mst1 renders mice predisposed to autoimmune disorders Fukuhara et al 2015;Halacli et al 2015;Thompson and Sahai 2015), and human studies suggest that single-nucleotide polymorphisms (SNPs) in Mst1 are associated with both Crohn's disease and colitis (Waterman et al 2011;Nimmo et al 2012). These observations indicate a potential negative function of Mst1 in autoimmunity and host defense.…”

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confidence: 99%

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Meng

Zhou

et al. 2016

Genes Dev.

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Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.

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“…Patients with MST1 deficiency have recurrent bacterial, viral, and fungal infections. Similar to DOCK8 deficient patients, they are especially prone to viral mucocutaneous infections . MST1 deficient patients have CD4 + T cell lymphopenia principally affecting naive T cells with decreased recent thymic emigrants .…”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

“…MST1 deficient patients also have hypergammaglobulinemia with variable response to vaccines . Unlike DOCK8 deficient patients, they tend to have normal to high percentages of memory B cells …”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Janssen

2018

Immunological Reviews

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Summary The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

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STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: A novel mutation

Cited by 77 publications

References 15 publications

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Primary immunodeficiencies caused by mutations in actin regulatory proteins

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