Identification of immune effectors and the post-translational modifications that control their activity is essential for dissecting mechanisms of immunity. Here we demonstrate that the antiviral activity of interferon-induced transmembrane protein 3 (IFITM3) is post-translationally regulated by S-palmitoylation. Large-scale profiling of palmitoylated proteins in a dendritic cell line using a chemical reporter strategy revealed over 150 lipid-modified proteins with diverse cellular functions, including innate immunity. We discovered that S-palmitoylation of IFITM3 on membrane-proximal cysteines controls its clustering in membrane compartments and its antiviral activity against influenza virus. The sites of S-palmitoylation are highly conserved among the IFITM family of proteins in vertebrates, which suggests that S-palmitoylation of these immune effectors may be an ancient post-translational modification that is crucial for host resistance to viral infections. The S-palmitoylation and clustering of IFITM3 will be important for elucidating its mechanism of action and for the design of antiviral therapeutics.Vertebrates have evolved sophisticated innate and adaptive mechanisms of immunity to combat microbial pathogens 1 . In response, viruses and pathogenic bacteria have acquired virulence factors that subvert or disarm host defenses 1 . For example, cellular membranes provide a simple barrier to infection, but viruses such as influenza virus have evolved specific proteins that fuse with membranes to allow viral replication inside host cells 2 . Alternatively, intracellular bacterial pathogens are taken up by phagocytic cells, but they then remodel cellular membranes to prevent their own degradation inside lysosomal compartments 3 . Cellular membranes are key interfaces for host resistance and prime targets for microbial virulence factors. We therefore performed large-scale profiling of palmitoylated proteins in phagocytic cells to identify membrane-associated proteins that contribute to immunity against microbial pathogens. We found that S-palmitoylation of interferon-induced transmembrane protein 3 (IFITM3) enhances its clustering in membranes * Correspondence and requests for materials should be addressed to H.C.H. hhang@rockefeller.edu. Author contributionsJ.S.Y. conceived the study, designed and performed experiments, interpreted data and co-wrote the manuscript; Y.-Y.Y. and G.C. synthesized reagents for palmitoylome profiling studies; B.M., C.B.L. and T.M.M. provided reagents and expertise on influenza virus infections; H.C.H. conceived the study, designed experiments, interpreted data and co-wrote the manuscript. Competing financial interestsThe authors declare no competing financial interests. Additional information RESULTS Proteomic analysis of palmitoylated proteins in DC2.4 cellsTo identify lipid-modified and membrane-associated proteins that may contribute to immune responses to microbial infections, we performed large-scale profiling of fatty-acylated proteins in the mouse DC line DC2.4 (ref. ...
Rationale AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism and an attractive drug target for cancer, metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMPK (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the utility of AMPK as a drug target. Objective We sought to identify the pro-growth signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. Methods and Results In a mouse model of N488I mutation of the Prkag2 (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular pre-excitation but did not affect the excessive cardiac growth in R2M mice. The pro-growth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mTOR and inactivation of FoxO signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mTOR activity by rapamycin or restoration of FoxO activity by overexpressing FoxO1 rescued the abnormal cardiac growth. Conclusions Our study reveals a novel mechanism for Prkag2 cardiomyopathy independent of glycogen storage. The role of γ2-AMPK in cell growth also has broad implications in cardiac development, growth and regeneration.
Background: For those patients who are not candidates for allogeneic stem cell transplantation (SCT) or who do not have an HLA-matched donor, it is unclear whether consolidation therapy with autologous SCT results in a survival benefit compared with further intensive post-remission non-myeloablative chemotherapy or no further therapy. Methods: A meta-analysis evaluating autologous SCT versus further chemotherapy or no treatment for acute myeloid leukemia (AML) in first complete remission (CR1) was completed. The search used the following combined search terms in Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library, the Web of Science and the China National Knowledge Infrastructure. Results: Overall, 13 studies of 12 randomized controlled trials were identified. Four studies were in pediatric patients and 9 were in adults. For adults, AML in CR1 compared with non-SCT, lower relapse and higher transplantation-related mortality were associated with autologous SCT, a significant disease-free survival benefit of autologous SCT was documented, and there was no difference in overall survival when studies were pooled. For pediatric AML in CR1, there were no differences in relapse, transplantation-related mortality, disease-free survival and overall survival. Significantly less survival from relapse impairment was found for autologous SCT. Conclusion: Our results support the conclusion that autologous SCT should not be considered as the first-line post-remission therapy for AML patients in CR1.
Background-Insulin resistance is associated with vascular disease. Physiological concentrations of insulin inhibit cultured vascular smooth muscle cell (VSMC) migration in the presence of nitric oxide, and the failure to do so in insulin-resistant states may aggravate vascular disease. We sought to determine the molecular mechanisms by which insulin inhibits VSMC migration. Methods and Results-Insulin at 1 nmol/L stimulated cGMP production in cultured rat VSMCs that were induced to express inducible nitric oxide synthase (iNOS). VSMC migration was measured in a wound-closure assay, and the platelet-derived growth factor-AB (
We have demonstrated that self-ordered porous alumina with large period can be obtained by stable anodization in citric acid at high voltage (400 V). Pore nucleation, which determines the final morphology of the alumina, is a very slow process. By comparing the alumina films obtained in different citric acid concentrations and temperatures, we found the amount of free citric acid anions is critical to pore nucleation. Surface chemistry and the detail structural composition of the porous alumina were investigated by XPS and TEM, respectively. The results show that uniform black alumina surface (forming ordered nanopores) cannot be obtained in low or high citric acid concentrations; the carbon element content of the black is obviously higher than that of gray surface (pores cannot well develop); citric acid is incorporated into the porous alumina cell, where the thickness ratio of compact skeleton and acid incorporated part is 1:3. Accordingly, the pore nucleation has two stages: I, fast forming flat barrier-type alumina film, alumina form and deposit at metal-oxide and oxide-electrolyte interface, respectively. II, Al-citric complex in electrolyte slowly transform to citric acid incorporated alumina and unevenly deposit on barrier-type alumina, which results in electric field concentration between protuberances and pore development.
Previous studies have shown that folate levels were decreased in patients with type 2 diabetes (T2D) and further lowered in T2D patients with cognitive impairment. However, whether folate deficiency could cause T2D and subsequent cognitive dysfunction is still unknown. The present study aimed to explore the effects of chronic folate deficiency (CFD) on glucose and lipid metabolism and cognitive function in mice. Seven-week-old mice were fed with either a CFD or control diet for 25 weeks. Serum folate was significantly reduced, whereas serum total homocysteine was significantly increased in the CFD group. Moreover, CFD induced obesity after a 6-week diet treatment, glucose intolerance and insulin resistance after a 16-week-diet treatment. In addition, CFD reduced the hepatic p-Akt/Akt ratio in response to acute insulin administration. Moreover, CFD increased serum triglyceride levels, upregulated hepatic Acc1 and Fasn mRNA expression, and downregulated hepatic Cd36 and ApoB mRNA expression. After a 24-week diet treatment, CFD induced anxiety-related activities and impairment of spatial learning and memory performance. This study demonstrates that folate deficiency could induce obesity, glucose and lipid metabolism disorders and subsequent cognitive dysfunction.
This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P < 0.001 and 50 % vs. 96 %, P = 0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462-96.218; P = 0.021) and PFS (HR, 6.073; 95 % CI, 1.082-34.085; P = 0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ (2) 23.079; P < 0.001) and distinct 3-year PFS rates (χ (2) 15.862; P < 0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.