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JCI Insight Sep 2020Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein...
Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.
Topics: Actins; Animals; Autoantibodies; Cells, Cultured; DNA; Dendritic Cells; Endosomes; Immunity, Innate; Interferons; Membrane Proteins; Mice; Mice, Inbred C57BL; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Wiskott-Aldrich Syndrome Protein
PubMed: 32721945
DOI: 10.1172/jci.insight.132857 -
Frontiers in Immunology 2022Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins,... (Review)
Review
Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.
Topics: Actin Cytoskeleton; Actins; Humans; Microfilament Proteins; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35371070
DOI: 10.3389/fimmu.2022.799309 -
Science Advances Apr 2023The higher-order assembly of Bin-amphiphysin-Rvs (BAR) domain proteins, including the FCH-BAR (F-BAR) domain proteins, into lattice on the membrane is essential for the...
The higher-order assembly of Bin-amphiphysin-Rvs (BAR) domain proteins, including the FCH-BAR (F-BAR) domain proteins, into lattice on the membrane is essential for the formation of subcellular structures. However, the regulation of their ordered assembly has not been elucidated. Here, we show that the higher ordered assembly of growth-arrested specific 7 (GAS7), an F-BAR domain protein, is regulated by the multivalent scaffold proteins of Wiskott-Aldrich syndrome protein (WASP)/neural WASP, that commonly binds to the BAR domain superfamily proteins, together with WISH, Nck, the activated small guanosine triphosphatase Cdc42, and a membrane-anchored phagocytic receptor. The assembly kinetics by fluorescence resonance energy transfer monitoring indicated that the GAS7 assembly on liposomes started within seconds and was further increased by the presence of these proteins. The regulated GAS7 assembly was abolished by Wiskott-Aldrich syndrome mutations both in vitro and in cellular phagocytosis. Therefore, Cdc42 and the scaffold proteins that commonly bind to the BAR domain superfamily proteins promoted GAS7 assembly.
Topics: Wiskott-Aldrich Syndrome Protein; Monomeric GTP-Binding Proteins; Wiskott-Aldrich Syndrome Protein, Neuronal; Nerve Tissue Proteins; Actins
PubMed: 37126564
DOI: 10.1126/sciadv.adf5143 -
Turkish Journal of Haematology :... Nov 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate...
OBJECTIVE
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort.
MATERIALS AND METHODS
We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019.
RESULTS
Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined.
CONCLUSION
All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Infant; Infant, Newborn; Male; Patient Outcome Assessment; Phenotype; Prognosis; Reinfection; Symptom Assessment; Treatment Outcome; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 32812413
DOI: 10.4274/tjh.galenos.2020.2020.0334 -
Experimental & Molecular Medicine Jun 2023The WAVE regulatory complex (WRC), composed of five components-Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300-is essential for proper actin cytoskeletal... (Review)
Review
The WAVE regulatory complex (WRC), composed of five components-Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300-is essential for proper actin cytoskeletal dynamics and remodeling in eukaryotic cells, likely by matching various patterned signals to Arp2/3-mediated actin nucleation. Accumulating evidence from recent studies has revealed diverse functions of the WRC in neurons, demonstrating its crucial role in dictating the assembly of molecular complexes for the patterning of various trans-synaptic signals. In this review, we discuss recent exciting findings on the physiological role of the WRC in regulating synaptic properties and highlight the involvement of WRC dysfunction in various brain disorders.
Topics: Actins; Wiskott-Aldrich Syndrome Protein Family; Carrier Proteins; Neurons
PubMed: 37258575
DOI: 10.1038/s12276-023-01004-1 -
Journal of Medical Case Reports Jul 2022Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections,...
INTRODUCTION
Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.
CASE PRESENTATION
We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott-Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.
CONCLUSION
Despite Wiskott-Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.
Topics: Africa, Eastern; Aged; Child; Humans; Immunoglobulin G; Infant; Male; Mutation; Reinfection; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35897083
DOI: 10.1186/s13256-022-03517-1 -
Frontiers in Immunology 2021Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the gene, which together with its homolog, N-, regulates actin...
Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the gene, which together with its homolog, N-, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of and its binding partner . Depletion of either or in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott-Aldrich syndrome.
Topics: Animals; Base Sequence; Biomarkers; Cell Line; Chromatin Immunoprecipitation Sequencing; Cytoskeletal Proteins; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Leukemia; Mice; Mice, Knockout; Promoter Regions, Genetic; Proto-Oncogene Protein c-fli-1; Signal Transduction; Thrombopoiesis; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33717090
DOI: 10.3389/fimmu.2021.607836 -
Frontiers in Immunology 2022Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have...
Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.
Topics: Animals; Cytokines; Homeostasis; Interleukin-17; Interleukin-4; Mice; Mice, Knockout; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35265075
DOI: 10.3389/fimmu.2022.817427 -
Experimental and Therapeutic Medicine Jan 2023Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infection and increased incidence of...
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infection and increased incidence of autoimmune disorders and malignancy. WAS is caused by mutations in the gene, which is expressed exclusively in hematopoietic cells; the spleen serves an important role in hematopoiesis and red blood cell clearance. However, to the best of our knowledge, detailed comparative analysis of the spleen between WASp-knockout (WAS-KO) and wild-type (WT) mice, particularly at the transcriptomic level, have not been reported. The present study investigated the differences in the transcriptomes of spleen tissue of 10-week-old WAS-KO mice. Comparison of the gene expression profiles of WAS-KO and WT mice revealed 1,964 differentially expressed genes (DEGs). Among these genes, 996 DEGs were upregulated and 968 were downregulated in WAS-KO mice. To determine the functions of DEGs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed for significantly upregulated and downregulated DEGs. The results showed that the levels of cell senescence and apoptosis-associated genes were increased, antigen processing and presentation mechanisms involved in the immune response were damaged and signal transduction processes were impaired in the spleen of WAS-KO mice. Thus, gene deletion may lead to anemia and hemolysis-associated disease, primarily due to increased osmotic fragility of red blood cells, low hemoglobin and increased bilirubin levels and serum ferritin. These results indicated that senescence and apoptosis of blood cells also play an important role in the occurrence of WAS. Therefore, the present findings provide a theoretical basis for further study to improve the treatment of WAS.
PubMed: 36605531
DOI: 10.3892/etm.2022.11763 -
Nature Communications Sep 2022
PubMed: 36075901
DOI: 10.1038/s41467-022-32875-z