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The Journal of Allergy and Clinical... Feb 2024Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated.
Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated.
PubMed: 38187865
DOI: 10.1016/j.jacig.2023.100191 -
BioRxiv : the Preprint Server For... Apr 2024Actin remodeling is spatiotemporally regulated by surface topographical cues on the membrane for signaling across diverse biological processes. Yet, the mechanism...
Actin remodeling is spatiotemporally regulated by surface topographical cues on the membrane for signaling across diverse biological processes. Yet, the mechanism dynamic membrane curvature prompts quick actin cytoskeletal changes in signaling remain elusive. Leveraging the precision of nanolithography to control membrane curvature, we reconstructed catalytic reactions from the detection of nano-scale curvature by sensing molecules to the initiation of actin polymerization, which is challenging to study quantitatively in living cells. We show that this process occurs via topographical signal-triggered condensation and activation of the actin nucleation-promoting factor (NPF), Neuronal Wiskott-Aldrich Syndrome protein (N-WASP), which is orchestrated by curvature-sensing BAR-domain protein FBP17. Such N-WASP activation is fine-tuned by optimizing FBP17 to N-WASP stoichiometry over different curvature radii, allowing a curvature-guided macromolecular assembly pattern for polymerizing actin network locally. Our findings shed light on the intricate relationship between changes in curvature and actin remodeling via spatiotemporal regulation of NPF/BAR complex condensation.
PubMed: 38712166
DOI: 10.1101/2024.04.25.591054 -
Biochimica Et Biophysica Acta.... Mar 2024The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of...
The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes. Male and female intestine-specific WASHC1-deficient mice (Washc1) were challenged with either a standard chow diet or a high-cholesterol (1.25 %) diet (HCD). Washc1 mice fed a standard diet did not present any apparent phenotype, but when fed an HCD, their hepatic cholesterol levels were ~ 50 % lower compared to those observed in control mice. The intestinal cholesterol absorption was almost 2-fold decreased in Washc1 mice, which translated into increased fecal neutral sterol loss. The intestinal expression of cholesterogenic genes, such as Hmgcs1, Hmgcr, and Ldlr, was significantly higher in Washc1 mice than in control mice and correlated with increased whole-body de novo cholesterol synthesis, likely to compensate for impaired intestinal cholesterol absorption. Unexpectedly, the ratio of biliary 12α-/non-12α-hydroxylated bile acids (BAs) was decreased in Washc1 mice and reversing this reduced ratio by feeding the mice with the HCD supplemented with 0.5 % (w/w) sodium cholate normalized the improvement of hepatic cholesterol levels in Washc1 mice. Our data indicate that the intestinal WASH complex plays an important role in intestinal cholesterol absorption, likely by modulating biliary BA composition.
Topics: Animals; Female; Humans; Male; Mice; Bile Acids and Salts; Biological Transport; Cholesterol; Intestines; Liver
PubMed: 38086439
DOI: 10.1016/j.bbalip.2023.159445 -
Cureus Jan 2024We present a case of a three-year-old African American male, born at term, who initially presented with bronchiolitis at six months and has since experienced recurrent...
Differential Diagnosis and Interdisciplinary Workup of a Pediatric Patient With an Unknown Immune Condition: Chronic Respiratory Distress Secondary to Viral Illness and Developmental Consequences.
We present a case of a three-year-old African American male, born at term, who initially presented with bronchiolitis at six months and has since experienced recurrent episodes of respiratory distress and hospitalizations. The patient also has severe eczema, developmental delays, and recurrent viral illnesses. Despite thorough evaluations from various specialists, such as pulmonology, allergy, and gastroenterology, the underlying cause remained elusive. The differential diagnosis for this case is as follows: severe persistent asthma with a possible link to genetic mutations such as CDHR3, hyper-IgE syndrome, atypical presentation of Wiskott-Aldrich syndrome, and severe gastroesophageal reflux disease (GERD) with aspiration pneumonitis. This patient's chronic condition has contributed to several developmental consequences, including failure to gain weight and possible hypoxic encephalopathy, leading to delays in cognitive and motor milestones and speech delays. Aggressive medical management, especially long-term systemic steroids, raises concerns about future complications. Through this case, we highlight the importance of thorough workups and an interdisciplinary approach to diagnosing and managing an unknown immune condition, as well as consistent pediatric primary care follow-up to assess development and coordinate necessary support. Here, we aim to address a gap in research on the unique presentations of pediatric respiratory distress symptoms by formulating a comprehensive differential diagnosis and exploring the various ways that chronic respiratory illness can contribute to developmental deficits such as speech and cognitive delays in pediatric patients. This study calls for further research into genetic contributions to asthma, diverse presentations of GERD, prevention of viral illnesses, alternative treatments minimizing steroid use, and an understanding of the impact of chronic respiratory distress on cognitive and language development in children. Thorough workups and interdisciplinary approaches are essential for effective diagnosis and management.
PubMed: 38414706
DOI: 10.7759/cureus.53109 -
Genes & Genetic Systems Mar 2024In Saccharomyces cerevisiae, boundaries formed by DNA sequence-dependent or -independent histone modifications stop the spread of the heterochromatin region formed via...
In Saccharomyces cerevisiae, boundaries formed by DNA sequence-dependent or -independent histone modifications stop the spread of the heterochromatin region formed via the Sir complex. However, it is unclear whether the histone modifiers that control DNA sequence-independent boundaries function in a chromosome-specific or -nonspecific manner. In this study, we evaluated the effects of the SAGA complex, a histone acetyltransferase (HAT) complex, and its relationship with other histone-modifying enzymes to clarify the mechanism underlying boundary regulation of the IMD2 gene on the right subtelomere of chromosome VIII. We found that Spt8, a component of the SAGA complex, is important for boundary formation in this region and that the inclusion of Spt8 in the SAGA complex is more important than its interaction with TATA-binding protein and TFIIS. In addition to SAGA, various HAT-related factors, such as NuA4 and Rtt109, also functioned in this region. In particular, the SAGA complex induced weak IMD2 expression throughout the cell, whereas NuA4 induced strong expression. These results indicate that multiple HATs contribute to the regulation of boundary formation and IMD2 expression on the right subtelomere of chromosome VIII and that IMD2 expression is determined by the balance between these factors.
Topics: Heterochromatin; Histone Acetyltransferases; Histones; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Wiskott-Aldrich Syndrome
PubMed: 38382924
DOI: 10.1266/ggs.23-00284 -
The Journal of Biological Chemistry Apr 2024The actin cytoskeleton and reactive oxygen species (ROS) both play crucial roles in various cellular processes. Previous research indicated a direct interaction between...
The actin cytoskeleton and reactive oxygen species (ROS) both play crucial roles in various cellular processes. Previous research indicated a direct interaction between two key components of these systems: the WAVE1 subunit of the WAVE regulatory complex (WRC), which promotes actin polymerization and the p47 subunit of the NADPH oxidase 2 complex (NOX2), which produces ROS. Here, using carefully characterized recombinant proteins, we find that activated p47 uses its dual Src homology 3 domains to bind to multiple regions within the WAVE1 and Abi2 subunits of the WRC, without altering WRC's activity in promoting Arp2/3-mediated actin polymerization. Notably, contrary to previous findings, p47 uses the same binding pocket to interact with both the WRC and the p22 subunit of NOX2, albeit in a mutually exclusive manner. This observation suggests that when activated, p47 may separately participate in two distinct processes: assembling into NOX2 to promote ROS production and engaging with WRC to regulate the actin cytoskeleton.
Topics: Humans; Actin Cytoskeleton; Actins; NADPH Oxidase 2; NADPH Oxidases; Protein Binding; Reactive Oxygen Species; Wiskott-Aldrich Syndrome Protein Family; Recombinant Proteins; Protein Subunits; Actin-Related Protein 2-3 Complex; Binding Sites
PubMed: 38432630
DOI: 10.1016/j.jbc.2024.107130 -
The Journal of Biological Chemistry Mar 2024Arp2/3 complex nucleates branched actin filaments that drive membrane invagination during endocytosis and leading-edge protrusion in lamellipodia. Arp2/3 complex is...
Arp2/3 complex nucleates branched actin filaments that drive membrane invagination during endocytosis and leading-edge protrusion in lamellipodia. Arp2/3 complex is maximally activated in vitro by binding of a WASP family protein to two sites-one on the Arp3 subunit and one spanning Arp2 and ARPC1-but the importance of each site in the regulation of force-producing actin networks is unclear. Here, we identify mutations in budding yeast Arp2/3 complex that decrease or block engagement of Las17, the budding yeast WASP, at each site. As in the mammalian system, both sites are required for maximal activation in vitro. Dimerization of Las17 partially restores activity of mutations at both CA-binding sites. Arp2/3 complexes defective at either site assemble force-producing actin networks in a bead motility assay, but their reduced activity hinders motility by decreasing actin assembly near the bead surface and by failing to suppress actin filament bundling within the networks. While even the most defective Las17-binding site mutants assembled actin filaments at endocytic sites, they showed significant internalization defects, potentially because they lack the proper architecture to drive plasma membrane remodeling. Together, our data indicate that both Las17-binding sites are important to assemble functional endocytic actin networks in budding yeast, but Arp2/3 complex retains some activity in vitro and in vivo even with a severe defect at either Las17-binding site.
Topics: Animals; Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Binding Sites; Mammals; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Wiskott-Aldrich Syndrome Protein
PubMed: 38367669
DOI: 10.1016/j.jbc.2024.105766