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Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in tw...
Citations
... The homeostasis and the function of T cells are frequently impaired with the absence of MST1 resulting that the hosts present susceptibility to the immunodeficiency syndrome, which causes various diseases because of recurrent bacterial and viral infections [13,41,56], such as lung infections, candidiasis, and non-degenerative skin warts [57]. Moreover, the deficiency of MST1 causes hypergammaglobulinemia with the production of autoantibody [42], which leads to the autoimmune diseases such as Sjogren's syndrome and colitis [14]; meanwhile, the hypergammaglobulinemia is associated with increased levels of IgG, IgA, and IgE [41]. ...
The mammalian Sterile 20-like kinase 1/2 (MST1/2) belongs to the serine/threonine (GC) protein kinase superfamily. Collective studies confirm the vital role MST1/2 in inflammation and immunity. MST1/2 is closely related to the progress of inflammation. Generally, MST1/2 aggravates the inflammatory injury through MST1-JNK, MST1-mROS, MST1-Foxo3, and NF-κB pathways, as well as several regulatory factors such as tumor necrosis factor-α (TNF-α), mitochondrial extension factor 1 (MIEF1), and lipopolysaccharide (LPS). Moreover, MST1/2 is also involved in the regulation of immunity to balance immune activation and tolerance by regulating MST1/2-Rac, MST1-Akt1/c-myc, MST1-Foxos, MST1-STAT, Btk pathways, and lymphocyte function-related antigen 1 (LFA-1), which subsequently prevents immunodeficiency syndrome and autoimmune diseases. This article reviews the effects of MST1/2 on inflammation and immunity.
... 16 STK4 de ciency is an autosomal recessive inherited combined immune de ciency which characterized with recurrent bacterial/viral infections, T cell lymphopenia, normal or mildly increased serum IgE levels and increase susceptibility to lymphoma in early age. [19][20][21][22][23] Despite STK4 is not included in classi cation of HIES, these patients can present as HIES phenotype especially similar phenotype to DOCK8 de ciency in early age with lymphopenia and severe recurrent viral skin infections by herpes family virus. 22,23 Fungal infections are not common ndings of these patients despite presence of severe T cell lymphopenia. ...
... STK4 de ciency is a rare combined primary immunode ciency which is characterized with recurrent infections, lymphopenia, increased susceptibility to malignancy. [19][20][21][22][23] There are around 32 reported patients with STK4 de ciency in the literature. 22 While STK4 de ciency has similar clinical and laboratory ndings to DOCK8 de ciency including recurrent infections, eczema, recurrent skin/systemic viral infections, lymphopenia and increased serum IgE level, DOCK8 de ciency can be easily diagnosed by absence of DOCK8 protein expression by owcytometry or western blot. ...
Background: Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency with overlapping features with the autosomal dominant (AD)– and recessive (AR) forms of the Hyper IgE syndrome (HIES), including recurrent infections, eczema, eosinophilia and elevated serum IgE levels. The precise distinguishing features of STK4 deficiency versus the different forms of HIES remain unclear.
Objective: We examined the comparative clinical and immunological features of STK4 deficiency versus AD- and AR forms of HIES, including signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8) respectively, with a focus on those attributes that distinguish STK4 deficiency from those disorders.
Methods: Six STK4, 4 STAT3 and 14 DOCK8 deficient patients and 16 healthy controls enrolled in this study. Clinical and immunological features of the patients including detailed analysis of naïve and memory T and B cell subsets including T helper (TH), T follicular helper (TFH) and T regulatory (Treg) cells were evaluated and compared with age matched control subjects.
Results: Recurrent infections and eczema were the most frequent clinical findings in AR- and eczema in AD-HIES. All STK4 deficient patients had recurrent herpetic facial lesions. Serum IgM level was significantly low in DOCK8 deficient patients compared to STAT3 and STK4 deficiency. Both CD4⁺T cell numbers and ratio were significantly lower in STK4 and DOCK8 deficient patients compared to control subjects. On the other hand, recent thymic emigrant (RTE) cell ratio was significantly lower, and T helper type 1 (TH1) cell frequencies were significantly higher in STK4 deficiency. While regulatory T (Treg) cell frequencies were significantly lower in DOCK8 deficiency, T helper type 17 (TH17) cell frequencies were significantly lower in both STAT3 and DOCK8 deficient patients.
Conclusion: While STK4 deficiency presents with overlapping clinical and immunological features with DOCK8 deficiency, including recurrent herpetic lesion and CD4⁺ T cell lymphopenia, it is distinguished by the absence of severe allergic diseases and by a number of immunological findings including decreased RTE and increased TH1 cell frequencies. STK4 deficiency should be considered in patients with AR-HIES with a clinical phenotype of DOCK8 deficiency but with otherwise normal DOCK8 protein expression.
... As the Hippo signaling pathway controls progenitor cell proliferation and differentiation, and the size of organs [23][24][25][26][27], the pathway is closely linked to mitochondrial energy metabolism and biogenesis. Studies suggest that the Hippo pathway modulates host antiviral immune responses [28][29][30][31][32][33], where YAP inhibits antiviral defense mechanisms by antagonizing the function of pro-innate immune factor TBK1 [34], which is a key signal transducer of cytosolic RNA-sensing retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) pathway. Inherited autosomal recessive mutations of MST1 (STK4) in human have been attributed to primary immunodeficiency with T-and B cell lymphopenia, neutropenia, and defective regulatory T cells [30,[35][36][37]. ...
... Furthermore, XMU-MP1 treatment stimulated an increase in SARS-CoV-2 replication. Similar to the activity of XMU-MP-1, MST1/2 loss of function mutations in humans result in immune deficiency disorders and the affected individuals are more susceptible to human papilloma infections [33]. Consistent with the clinical observation, our study indicates that pharmacological inhibition of MST1/2 promotes the susceptibility of cardiac and lung cells to SARS-CoV-2 infection. ...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19-associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin, a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.
... Patients with global STK4 deficiency suffer from recurrent infections, immune dysregulation, and autoimmunity (8,(16)(17)(18). Studies in mice have revealed different roles for Stk3/4 in T cell and dendritic cell responses (19,20). ...
The molecular programs involved in regulatory T (T reg ) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T reg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4–NF-κB p65–Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in T reg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased T reg cell p65 expression and nuclear translocation, impaired NF-κB p65–Foxp3 complex formation, and defective T reg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3 S418E in Stk3/4-deficient T reg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3–dependent transcription that promotes T reg cell–mediated immune tolerance.
... More specifically, patients present with Hodgkin B cell lymphoma [2], extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue [8], Burkitt's lymphoma [7], or maxillary sinus diffuse large B cell lymphoma [9]. Additional clinical features in patients with STK4 deficiency include salt-losing tubulopathy, suggestive of an acquired Gitelman syndrome, immune complex glomerulonephritis, and Castleman-like disease [10], juvenile idiopathic arthritis [11], human beta-papillomavirus-associated epidermodysplasia verruciformis [11,12], primary cardiac T cell lymphoma [6], and short stature [13]. ...
Purpose
Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.
Methods
The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing.
Results
The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein–Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens.
Conclusion
Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.
... Through the non-canonical Hippo pathway, STK4 exerts a variety of other functions on immune cells, such as extravasation and vesicle trafficking of neutrophils [74,137], humoral immunity [77] and T cell migration, development, and function [76,138,139]. T cells from STK4-deficient patients show reduced proliferation upon stimulation [69][70][71][72][73][74][75][76][77][78][79][80]. Nehme et al. could link decreased T cell proliferation with elevated T cell apoptosis due to increased FAS expression on the T cell surface [78]. ...
Epstein–Barr Virus (EBV) is a ubiquitous virus affecting more than 90% of the world’s population. Upon infection, it establishes latency in B cells. It is a rather benign virus for immune-competent individuals, in whom infections usually go unnoticed. Nevertheless, EBV has been extensively associated with tumorigenesis. Patients suffering from certain inborn errors of immunity are at high risk of developing malignancies, while infection in the majority of immune-competent individuals does not seem to lead to immune dysregulation. Herein, we discuss how inborn mutations in TNFRSF9, CD27, CD70, CORO1A, CTPS1, ITK, MAGT1, RASGRP1, STK4, CARMIL2, SH2D1A, and XIAP affect the development, differentiation, and function of key factors involved in the immunity against EBV, leading to increased susceptibility to lymphoproliferative disease and lymphoma.
... More specifically, patients present with Hodgkin B cell lymphoma [2], extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue [8], Burkitt's lymphoma [7], or maxillary sinus diffuse large B cell lymphoma [9]. Additional clinical features in patients with STK4 deficiency include salt-losing tubulopathy, suggestive of an acquired Gitelman syndrome, immune complex glomerulonephritis, and Castleman-like disease [10], juvenile idiopathic arthritis [11], human beta-papillomavirus-associated epidermodysplasia verruciformis [11,12], primary cardiac T cell lymphoma [6], and short stature [13]. ...
... Approximately two thirds of EV cases are due to autosomal recessive mutations in EVER1 AND 2 [55], encoded by transmembrane channel-like 6 and 8, respectively (TMC6 and TMC8). EVER1 and 2 genes are expressed in keratinocytes and leukocytes [56,57]. The cellular and molecular basis of EV disease in EVER deficient patients is still unknown [54]. ...
... The cellular and molecular basis of EV disease in EVER deficient patients is still unknown [54]. EVER genes encode endoplasmic reticulum transmembrane proteins [55] and may be involved in the regulation of cellular zinc homeostasis in lymphocytes [51,56,57]. They are thought to be restriction factors for beta-HPVs in keratinocytes. ...
... Some patients with atypical EV have also been described to have growth retardation, mild developmental delay, as well as autoimmune features [54]. Mutations in RHOH and STK4 (encoding macrophage stimulating 1 (MST1)) have been found in patients with the atypical EV phenotype [57]. Patients with autosomal recessive RHOH deficiency have been described to have T-cell defects, including low numbers of naïve T cells, high numbers of memory T cells, and impaired antigen-induced and anti-CD3-induced T-cell proliferation. ...
The innate immune system is the host’s first line of defense against pathogens. Toll-like receptors (TLRs) are pattern recognition receptors that mediate recognition of pathogen-associated molecular patterns. TLRs also activate signaling transduction pathways involved in host defense, inflammation, development, and the production of inflammatory cytokines. Innate immunodeficiencies associated with defective TLR signaling include mutations in NEMO, IKBA, MyD88, and IRAK4. Other innate immune defects have been associated with susceptibility to herpes simplex encephalitis, viral infections, and mycobacterial disease, as well as chronic mucocutaneous candidiasis and epidermodysplasia verruciformis. Phagocytes and natural killer cells are essential members of the innate immune system and defects in number and/or function of these cells can lead to recurrent infections. Complement is another important part of the innate immune system. Complement deficiencies can lead to increased susceptibility to infections, autoimmunity, or impaired immune complex clearance. The innate immune system must work to quickly recognize and eliminate pathogens as well as coordinate an immune response and engage the adaptive immune system. Defects of the innate immune system can lead to failure to quickly identify pathogens and activate the immune response, resulting in susceptibility to severe or recurrent infections.
... Finally, deficiencies in more indirect regulators of actin cytoskeleton dynamics have been associated to PID entities. This includes CD2BP1/PSTPIP1 (Wise et al., 2002), MST1/STK4 (Crequer et al., 2012a;Nehme et al., 2012), NIK (Willmann et al., 2014), MKL1 (Record et al., 2015) and RasGRP1 (Salzer et al., 2016;Winter et al., 2018). These PID-related proteins build a molecular network that covers key aspects of the actin remodeling machinery (Figure 3). ...
The actin cytoskeleton is composed of dynamic filament networks that build adaptable local architectures to sustain nearly all cellular activities in response to a myriad of stimuli. Although the function of numerous players that tune actin remodeling is known, the coordinated molecular orchestration of the actin cytoskeleton to guide cellular decisions is still ill defined. T lymphocytes provide a prototypical example of how a complex program of actin cytoskeleton remodeling sustains the spatio-temporal control of key cellular activities, namely antigen scanning and sensing, as well as polarized delivery of effector molecules, via the immunological synapse. We here review the unique knowledge on actin dynamics at the T lymphocyte synapse gained through the study of primary immunodeficiences caused by mutations in genes encoding actin regulatory proteins. Beyond the specific roles of individual actin remodelers, we further develop the view that these operate in a coordinated manner and are an integral part of multiple signaling pathways in T lymphocytes.
... The mechanisms of individual susceptibility to D and SD remains unclear, but host genetics implicate immune response (ACT1, C5, IKBKG/NEMO, STK4) and epidermal differentiation (ZNF750). However, it is still not known how disruption to these genetic factors is related to the clinical presentation of D and SD (Jacobs and Miller, 1972;Evans et al., 1977;Mancini et al., 2008;Abdollahpour et al., 2012;Crequer et al., 2012;Nehme et al., 2012;Boisson et al., 2013;Halacli et al., 2015;Karakadze et al., 2018). ...
The skin microbial community is a multifunctional ecosystem aiding prevention of infections from transient pathogens, maintenance of host immune homeostasis, and skin health. A better understanding of the complex milieu of microbe-microbe and host-microbe interactions will be required to define the ecosystem’s optimal function and enable rational design of microbiome targeted interventions. Malassezia, a fungal genus currently comprising 18 species and numerous functionally distinct strains, are lipid-dependent basidiomycetous yeasts and integral components of the skin microbiome. The high proportion of Malassezia in the skin microbiome makes understanding their role in healthy and diseased skin crucial to development of functional skin health knowledge and understanding of normal, healthy skin homeostasis. Over the last decade, new tools for Malassezia culture, detection, and genetic manipulation have revealed not only the ubiquity of Malassezia on skin but new pathogenic roles in seborrheic dermatitis, psoriasis, Crohn’s disease, and pancreatic ductal carcinoma. Application of these tools continues to peel back the layers of Malassezia/skin interactions, including clear examples of pathogenicity, commensalism, and potential protective or beneficial activities creating mutualism. Our increased understanding of host- and microbe-specific interactions should lead to identification of key factors that maintain skin in a state of healthy mutualism or, in turn, initiate pathogenic changes. These approaches are leading toward development of new therapeutic targets and treatment options. This review discusses recent developments that have expanded our understanding of Malassezia’s role in the skin microbiome, with a focus on its multiple roles in health and disease as commensal, pathogen, and protector.
