Lipid rafts are cholesterol-rich membrane microdomains that are thought to act as coordinated signaling platforms by regulating dynamic, agonist-induced translocation of signaling proteins. They have been described to play a role in multiple prototypical cascades, among them the lipopolysaccharide pathway, and to host multiple signaling proteins, including kinases and low molecular weight G-proteins. Here we report lipopolysaccharide-induced activation of the Rho family GTPase Cdc42, and we show its activation in the human neutrophil to be mediated by a p38 mitogen-activated protein kinase-dependent mechanism. Subcellular fractionation reveals that lipopolysaccharide induces translocation of Cdc42 to lipid rafts, where it and p38 are both found to be activated. By contrast, lipopolysaccharide causes translocation of Rac from the polymorphonuclear leukocyte (PMN) rafts and does not induce its activation. With the use of methyl-beta-cyclodextrin, a cholesterol-depleting agent that reversibly disrupts rafts, we confirm an important regulatory role for rafts in the activation state of p38 and Cdc42 and in the Rho GTPase-dependent functions superoxide anion production and actin polymerization. Methyl-beta-cyclodextrin induces activation of p38 and Cdc42, but not Rac, in the nonstimulated PMN, yet inhibits subsequent lipopolysaccharide-induced activation of p38 and Cdc42. In parallel, methyl-beta-cyclodextrin primes the human PMN for subsequent superoxide release triggered by the formylated bacterial tripeptide formyl-Met-Leu-Phe, and induces actin polymerization in a subcellular distribution distinct from that induced by lipopolysaccharide. In sum, these findings provide evidence for an important regulatory role of cholesterol in both transmission of the lipopolysaccharide signal and the inflammatory phenotype of the human neutrophil.
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http://dx.doi.org/10.1074/jbc.M401080200 | DOI Listing |
Front Immunol
January 2025
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint swelling, pain, and bone remodeling. We previously reported that autotaxin (ATX) deficiency disrupts lipid rafts in macrophages. Lipid raft disruption results in the dysregulation of RANK signaling, which is crucial for osteoclastogenesis and the pathogenesis of RA.
View Article and Find Full Text PDFInt J Pharm
December 2024
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China; Faculty of Health Sciences, University of Macau, Macau 999078, China. Electronic address:
Messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNPs) represents a cutting-edge delivery technology that played a pivotal role during the COVID-19 pandemic and in advancing vaccine development. However, molecular structure of mRNA-LNPs at real size remains poorly understood, with conflicting results from various experimental studies. In this study, we aim to explore the assembly process and structural characteristics of mRNA-LNPs at realistic sizes using coarse-grained molecular dynamic simulations.
View Article and Find Full Text PDFBiologics
December 2024
Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
Purpose: Chronic suppurative otitis media (CSOM) is a prominent contributor to preventable hearing loss globally. Probiotic therapy has attracted research interest in human infectious and inflammatory disease. As the most prevalent probiotic, the role of in CSOM remains poorly defined.
View Article and Find Full Text PDFFEBS J
December 2024
School of Veterinary Medicine, Azabu University, Sagamihara, Japan.
Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease, posing a high risk of mortality. Sphingomyelin, a sphingolipid synthesized by sphingomyelin synthases (SMSs) 1 and 2, plays an essential role in signal transduction as a component of lipid rafts. However, the role of sphingomyelin in the inflammation of ischemic skeletal muscles remains unclear.
View Article and Find Full Text PDFBiochem Biophys Res Commun
December 2024
Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
Lipid rafts are subdomains of the cell membrane that are rich in cholesterol and glycolipids, and they are involved in various cellular processes and pathophysiological mechanisms. However, the specific role of lipid rafts in hepatocyte dysfunction during the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is not fully understood. In this study, we investigated the impact of lipid rafts on insulin sensitivity and hepatocyte injury induced by saturated free fatty acids (sFFAs) using primary-cultured mouse hepatocytes.
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