Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor.
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http://dx.doi.org/10.4049/jimmunol.1302411 | DOI Listing |
Am J Physiol Regul Integr Comp Physiol
December 2024
Curtin University, Curtin Medical Research Institute (Bentley, WA, AUSTRALIA).
Physical activity improves myocardial structure, function and resilience via complex, incompletely defined mechanisms. We explored effects of 1-2 wks swim training on cardiac and systemic phenotype in young male C57Bl/6 mice. Two wks forced swimming (90 min twice daily) resulted in cardiac hypertrophy (22% increase in heart:body weight, P<0.
View Article and Find Full Text PDFViral Immunol
January 2025
Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico.
Respiratory syncytial virus (RSV) is one of the most important etiologies of acute respiratory infections that cause bronchiolitis in children under 5 years of age. Treatments are expensive, no vaccine is available, and this is an important cause of hospitalization. Costimulatory molecules have been reported to be good inducers of antiviral type 1 immune response.
View Article and Find Full Text PDFIn Vitro Cell Dev Biol Anim
January 2025
Department of Biology, Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON, N2L 3C5, Canada.
Long dsRNA induces the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) to establish an antiviral state. When induced prophylactically, this antiviral state can reduce the severity and mortality of viral infections. One of the limiting factors in delivering dsRNA in animal models is the lack of an effective carrier that protects the dsRNA from degradation in the extracellular space.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Florida College of Medicine, Gainesville, FL, USA.
Background: Peripheral blood mononuclear cells (PBMCs) were obtained from patients across different stages of Parkinson's disease (PD) progression and stimulated ex vivo to develop biomarkers for predicting PD progression.
Method: PBMCs obtained at one time-point from patients with moderate stage PD (>5 years after diagnosis) (n = 30), early stage PD (<5 years after diagnosis) (n = 27), prodromal PD (rapid-eye-movement sleep behavior disorder patients) (n = 14), and healthy controls (HCs) (n = 9) were isolated from whole blood and cryopreserved. Samples were thawed, then pan-monocytes and T-cell populations were isolated from PBMCs and subjected to treatment with vehicle or IFN-γ.
Int J Biol Sci
January 2025
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China.
FAT atypical cadherin 1 (), which encodes an atypical cadherin-coding protein, has a high mutation rate and is commonly regarded as a tumor suppressor gene in head and neck squamous cell carcinoma (HNSCC). Nonetheless, the potential regulatory mechanisms by which FAT1 influences the progression of HNSCC remain unresolved. In this context, we reported that FAT1 was downregulated in tumor tissues/cells compared with normal tissues/cells and that it was correlated with the clinicopathological features and prognosis of HNSCC.
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