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Oncoimmunology 2018The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with...
The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To understand the role of WASp in tumorigenesis, we bred WASp, WASp, and WASp-XLN mice onto tumor susceptible p53 background and sub-lethally irradiated them to enhance tumor development. We followed the cohorts for 24 weeks and tumors were characterized by histology and flow cytometry to define the tumor incidence, onset, and cell origin. We found that p53WASp mice developed malignancies, including solid tumors and T cell lymphomas with 71.4% of survival 24 weeks after irradiation. p53WASp mice showed lower survival rate and developed various early onset malignancies. Surprisingly, the p53WASp-XLN mice developed malignancy mostly with late onset, which caused delayed mortality in this colony. This study provides evidence for that loss-of-function and gain-of-function mutations in WASp influence tumor incidence and onset.
PubMed: 30393584
DOI: 10.1080/2162402X.2018.1468954 -
Frontiers in Immunology 2022Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic... (Review)
Review
Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic hematopoietic stem cell transplantation and with experimental autologous gene therapy. With both approaches still facing important challenges, gene editing has recently emerged as a potential valuable alternative for the treatment of genetic disorders and within a relatively short period from its initial development, has already entered some landmark clinical trials aimed at tackling several life-threatening diseases. In this review, we discuss the progress made towards the development of gene editing-based therapeutic strategies for PIDs with a special focus on Wiskott - Aldrich syndrome and outline their main challenges as well as future directions with respect to already established treatments.
Topics: Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 36059471
DOI: 10.3389/fimmu.2022.966084 -
ELife Nov 2020The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune...
The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
Topics: Autophagy; Cell Line; Gene Expression Regulation; Homeostasis; Humans; Macrophages; Mitochondria; Wiskott-Aldrich Syndrome Protein
PubMed: 33135633
DOI: 10.7554/eLife.55547 -
Frontiers in Immunology 2021Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to... (Review)
Review
Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA. Hence, understanding how cellular mechanism controls the pathogenic responses to self-nucleic acid has important clinical implications. Fine-tuned membrane trafficking and cellular compartmentalization are two major factors that balance activation of DNA sensors and availability of self-DNA ligands. Intracellular transport and organelle architecture are in turn regulated by cytoskeletal dynamics, yet the precise impact of actin remodeling on DNA sensing remains elusive. This review proposes a critical analysis of the established and hypothetical connections between self-DNA recognition and actin dynamics. As a paradigm of this concept, we discuss recent evidence of deregulated self-DNA sensing in the prototypical actin-related primary immune deficiency (Wiskott-Aldrich syndrome). We anticipate a broader impact of actin-dependent processes on tolerance to self-DNA in autoimmune disorders.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cytoskeleton; DNA; Endosomes; Humans; Membrane Proteins; Nucleotidyltransferases; Phagocytes; Protein Binding; Protein Transport; Signal Transduction; Toll-Like Receptor 9
PubMed: 34084165
DOI: 10.3389/fimmu.2021.657344 -
Intractable & Rare Diseases Research Feb 2024Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS....
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS. In this work, we report a boy who presented with intracranial hemorrhage (ICH) as an initial symptom and detects a novel pathogenic synonymous mutation in his gene. His mother was a carrier of the mutant gene. The mutation, located at position c.273 (c.273 G>A) in exon 2, is a synonym mutation and predicted to affect protein expression by disrupting gene splicing. This study summarizes the diagnosis and treatment process of the patient and expands the genetic spectrum of WAS.
PubMed: 38404734
DOI: 10.5582/irdr.2023.01102 -
British Journal of Haematology Jan 2021
Topics: Child; Humans; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin; Wiskott-Aldrich Syndrome
PubMed: 33280084
DOI: 10.1111/bjh.17171 -
Journal of Experimental & Clinical... Apr 2022Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Wiskott-Aldrich syndrome protein family member 2 (WASF2) is an integral member of...
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Wiskott-Aldrich syndrome protein family member 2 (WASF2) is an integral member of the actin cytoskeleton pathway, which plays a crucial role in cell motility. In this study, we aimed to explore the role of WASF2 in HCC carcinogenesis and its regulatory mechanism.
METHODS
WASF2 expression in HCC was analyzed using six public RNA-seq datasets and 66 paired tissues from patients with HCC. The role of WASF2 in normal hepatocyte cell phenotypes was evaluated using a WASF2 overexpression vector in vitro; it was evaluated in HCC cell phenotypes using small interfering RNA (siRNA) in vitro and in vivo. Epigenetic regulatory mechanism of WASF2 was assessed in the Cancer Genome Atlas liver hepatocellular carcinoma project (TCGA_LIHC) dataset and also validated in 38 paired HCC tissues. Site mutagenesis, bisulfite sequencing polymerase chain reaction (BSP), methylation-specific polymerase chain reaction (MSP), and quantitative MSP (qMSP) were used for evaluating WASF2 methylation status.
RESULTS
WASF2 is overexpressed in HCC and is clinically correlated with its prognosis. WASF2 overexpression promoted normal hepatocyte proliferation. WASF2 inactivation decreased the viability, growth, proliferation, migration, and invasion of Huh-7 and SNU475 HCC cells by inducing G2/M phase arrest. This induced cell death and inhibited epithelial-mesenchymal transition, hindering actin polymerization. In addition, WASF2 knockdown using siWASF2 in a xenograft mouse model and a lung metastasis model exerted tumor suppressive effect. There was a negative correlation between WASF2 methylation status and mRNA expression. The methylation pattern of CpG site 2 (- 726 bp), located in the WASF2 promoter, plays an important role in the regulation of WASF2 expression. Furthermore, the cg242579 CpG island in the WASF2 5' promoter region was hypomethylated in HCC compared to that in the matched non-tumor samples. Patients with high WASF2 methylation and low WASF2 expression displayed the highest overall survival.
CONCLUSIONS
WASF2 is overexpressed and hypomethylated in HCC and correlates with patient prognosis. WASF2 inactivation exerts anti-tumorigenic effects on HCC cells in vitro and in vivo, suggesting that WASF2 could be a potential therapeutic target for HCC.
Topics: Animals; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mice; Promoter Regions, Genetic; Up-Regulation; Wiskott-Aldrich Syndrome Protein Family
PubMed: 35477411
DOI: 10.1186/s13046-022-02365-7 -
Journal of Cell Science Jul 2017Proteins of the Wiskott-Aldrich syndrome protein (WASP) family function as nucleation-promoting factors for the ubiquitously expressed Arp2/3 complex, which drives the... (Review)
Review
Proteins of the Wiskott-Aldrich syndrome protein (WASP) family function as nucleation-promoting factors for the ubiquitously expressed Arp2/3 complex, which drives the generation of branched actin filaments. Arp2/3-generated actin regulates diverse cellular processes, including the formation of lamellipodia and filopodia, endocytosis and/or phagocytosis at the plasma membrane, and the generation of cargo-laden vesicles from organelles including the Golgi, endoplasmic reticulum (ER) and the endo-lysosomal network. Recent studies have also identified roles for WASP family members in promoting actin dynamics at the centrosome, influencing nuclear shape and membrane remodeling events leading to the generation of autophagosomes. Interestingly, several WASP family members have also been observed in the nucleus where they directly influence gene expression by serving as molecular platforms for the assembly of epigenetic and transcriptional machinery. In this Cell Science at a Glance article and accompanying poster, we provide an update on the subcellular roles of WHAMM, JMY and WASH (also known as WASHC1), as well as their mechanisms of regulation and emerging functions within the cell.
Topics: Humans; Wiskott-Aldrich Syndrome Protein Family
PubMed: 28646090
DOI: 10.1242/jcs.199570 -
Frontiers in Immunology 2021Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic... (Review)
Review
Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.
Topics: Agammaglobulinemia; Alleles; Biomarkers; Diagnosis, Differential; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mosaicism; Mutation; Organ Specificity; Phenotype; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Wiskott-Aldrich Syndrome
PubMed: 34868061
DOI: 10.3389/fimmu.2021.783022 -
BioRxiv : the Preprint Server For... Oct 2023Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition...
Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL's mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.
PubMed: 37873483
DOI: 10.1101/2023.10.02.560434