scholarly journals Stat-mediated Signaling Induced by Type I and Type II Interferons (IFNs) Is Differentially Controlled through Lipid Microdomain Association and Clathrin-dependent Endocytosis of IFN Receptors

2006 ◽  
Vol 17 (7) ◽  
pp. 2896-2909 ◽  
Author(s):  
Marta Marchetti ◽  
Marie-Noelle Monier ◽  
Alexandre Fradagrada ◽  
Keith Mitchell ◽  
Florence Baychelier ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Biological Activities ◽  
Critical Role ◽  
Membrane Lipid ◽  
Endocytic Pathway ◽  
Type I ◽  
Type Ii ◽  
Biological Responses ◽  
Signal Specificity ◽  
Ifn Γ

Type I (α/β) and type II (γ) interferons (IFNs) bind to distinct receptors, although they activate the same signal transducer and activator of transcription, Stat1, raising the question of how signal specificity is maintained. Here, we have characterized the sorting of IFN receptors (IFN-Rs) at the plasma membrane and the role it plays in IFN-dependent signaling and biological activities. We show that both IFN-α and IFN-γ receptors are internalized by a classical clathrin- and dynamin-dependent endocytic pathway. Although inhibition of clathrin-dependent endocytosis blocked the uptake of IFN-α and IFN-γ receptors, this inhibition only affected IFN-α–induced Stat1 and Stat2 signaling. Furthermore, the antiviral and antiproliferative activities induced by IFN-α but not IFN-γ were also affected. Finally, we show that, unlike IFN-α receptors, activated IFN-γ receptors rapidly become enriched in plasma membrane lipid microdomains. We conclude that IFN-R compartmentalization at the plasma membrane, through clathrin-dependent endocytosis and lipid-based microdomains, plays a critical role in the signaling and biological responses induced by IFNs and contributes to establishing specificity within the Jak/Stat signaling pathway.

scholarly journals Offloading Role of a Discrete Thioesterase in Type II Polyketide Biosynthesis

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Kangmin Hua ◽  
Xiangyang Liu ◽  
Yuchun Zhao ◽  
Yaojie Gao ◽  
Lifeng Pan ◽  
...  
Keyword(s):  
Acyl Carrier Protein ◽  
Biological Activities ◽  
Condensation Reaction ◽  
Critical Role ◽  
Shake Flask Culture ◽  
Type Ii ◽  
Batch Mode ◽  
Polyketide Biosynthesis ◽  
Thioester Bond ◽  
Polyketide Chain

ABSTRACT Type II polyketides are a group of secondary metabolites with various biological activities. In nature, biosynthesis of type II polyketides involves multiple enzymatic steps whereby key enzymes, including ketoacyl-synthase (KSα), chain length factor (KSβ), and acyl carrier protein (ACP), are utilized to elongate the polyketide chain through a repetitive condensation reaction. During each condensation, the biosynthesis intermediates are covalently attached to KSα or ACP via a thioester bond and are then cleaved to release an elongated polyketide chain for successive postmodification. Despite its critical role in type II polyketide biosynthesis, the enzyme and its corresponding mechanism for type II polyketide chain release through thioester bond breakage have yet to be determined. Here, kinamycin was used as a model compound to investigate the chain release step of type II polyketide biosynthesis. Using a genetic knockout strategy, we confirmed that AlpS is required for the complete biosynthesis of kinamycins. Further in vitro biochemical assays revealed high hydrolytic activity of AlpS toward a thioester bond in an aromatic polyketide-ACP analog, suggesting its distinct role in offloading the polyketide chain from ACP during the kinamycin biosynthesis. Finally, we successfully utilized AlpS to enhance the heterologous production of dehydrorabelomycin in Escherichia coli by nearly 25-fold, which resulted in 0.50 g/liter dehydrorabelomycin in a simple batch-mode shake flask culture. Taken together, our results provide critical knowledge to gain an insightful understanding of the chain-releasing process during type II polyketide synthesis, which, in turn, lays a solid foundation for future new applications in type II polyketide bioproduction.

scholarly journals Potent Inhibition of SARS-Associated Coronavirus (SCoV) Infection and Replication by Type I Interferons (IFN-α/β) but Not by Type II Interferon (IFN-γ)

2004 ◽  
Vol 24 (7) ◽  
pp. 388-390 ◽  
Author(s):  
Bojian Zheng ◽  
Ming-Liang He ◽  
King-Ling Wong ◽  
Ching Tung Lum ◽  
Leo L.M. Poon ◽  
...  
Keyword(s):  
Type I Interferons ◽  
Type I ◽  
Type Ii ◽  
Potent Inhibition ◽  
Ifn Γ

scholarly journals Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Chuan Xia ◽  
Jennifer J. Wolf ◽  
Madhuvanthi Vijayan ◽  
Caleb J. Studstill ◽  
Wenjun Ma ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
P38 Map Kinase ◽  
Casein Kinase ◽  
Type I ◽  
Type Ii ◽  
Ifn Γ ◽  
Cellular Responsiveness ◽  
Novel Strategy

ABSTRACTAlthough influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs. IAV infection or transient HA expression induced degradation of both IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate the receptors. IAV HA caused the phosphorylation and ubiquitination of IFNGR1, leading to the lysosome-dependent degradation of IFNGR1. Influenza viral HA strongly decreased cellular sensitivity to type II IFNs, as it suppressed the activation of STAT1 and the induction of IFN-γ-stimulated genes in response to exogenously supplied recombinant IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2, was proven to be critical for HA-induced degradation of both IFNGR1 and IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA (siRNA)-based knockdown of CK1α repressed the degradation processes of both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was shown to be pivotal for proficient replication of IAV. Collectively, the results suggest that IAV HA induces degradation of IFN receptors via CK1α, creating conditions favorable for viral propagation. Therefore, the study uncovers a new immune-evasive pathway of influenza virus.IMPORTANCEInfluenza A virus (IAV) remains a grave threat to humans, causing seasonal and pandemic influenza. Upon infection, innate and adaptive immunity, such as the interferon (IFN) response, is induced to protect hosts against IAV infection. However, IAV seems to be equipped with tactics to evade the IFN-mediated antiviral responses, although the detailed mechanisms need to be elucidated. In the present study, we show that IAV HA induces the degradation of the type II IFN receptor IFNGR1 and thereby substantially attenuates cellular responses to IFN-γ. Of note, a cellular kinase, casein kinase 1α (CK1α), is crucial for IAV HA-induced degradation of both IFNGR1 and IFNAR1. Accordingly, CK1α is proven to positively regulate IAV propagation. Thus, this study unveils a novel strategy employed by IAV to evade IFN-mediated antiviral activities. These findings may provide new insights into the interplay between IAV and host immunity to impact influenza virus pathogenicity.

Activation of the Transcription Factor ISGF3 by Interferon-gamma

1999 ◽  
Vol 380 (6) ◽  
pp. 699-703 ◽  
Author(s):  
M. Matsumoto ◽  
N. Tanaka ◽  
H. Harada ◽  
T. Kimura ◽  
T. Yokochi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Type I ◽  
Type Ii ◽  
Additional Mechanism ◽  
Embryonic Fibroblasts ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Antiviral Activities ◽  
Ifn Γ ◽  
Binding Component

AbstractThe interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-α/β)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-γ) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-γ stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-α/β and -γ, can commonly elicit antiviral activities.

Acute Liver Failure Following Minocycline Treatment – A Case Report and Review of the Literature

2012 ◽  
Vol 50 (08) ◽  
pp. 771-775 ◽  
Author(s):  
A. Kuhn ◽  
C. Weiler-Normann ◽  
C. Schramm ◽  
S. Kluge ◽  
M. Behne ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Studies ◽  
Type I ◽  
Type Ii ◽  
Minocycline Treatment ◽  
Tnf Α ◽  
Ige Mediated ◽  
Ifn Γ

AbstractWe present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

scholarly journals Interferon Regulatory Factor 1 Protects against Chikungunya Virus-Induced Immunopathology by Restricting Infection in Muscle Cells

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Sharmila Nair ◽  
Subhajit Poddar ◽  
Raeann M. Shimak ◽  
Michael S. Diamond
Keyword(s):  
Chikungunya Virus ◽  
Muscle Cells ◽  
Interferon Regulatory Factor ◽  
Ross River Virus ◽  
Type I ◽  
Type Ii ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Ifn Γ

ABSTRACT The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of alpha/beta interferon (IFN-α/β) (type I), IFN-γ (type II), and IFN-λ (type III). The transcription factor interferon regulatory factor 1 (IRF-1) has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN-stimulated genes (ISGs) and mediating signals downstream of IFN-γ. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role in vivo remains unknown. Here, we infected Irf1 −/− mice with two distantly related arthritogenic alphaviruses, chikungunya virus (CHIKV) and Ross River virus (RRV), and assessed the early antiviral functions of IRF-1 prior to induction of adaptive B and T cell responses. IRF-1 expression limited CHIKV-induced foot swelling in joint-associated tissues and prevented dissemination of CHIKV and RRV at early time points. Virological and histological analyses revealed greater infection of muscle tissues in Irf1 −/− mice than in wild-type mice. The antiviral actions of IRF-1 appeared to be independent of the induction of type I IFN or the effects of type II and III IFNs but were associated with altered local proinflammatory cytokine and chemokine responses and differential infiltration of myeloid cell subsets. Collectively, our in vivo experiments suggest that IRF-1 restricts CHIKV and RRV infection in stromal cells, especially muscle cells, and that this controls local inflammation and joint-associated swelling. IMPORTANCE Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates the expression of a broad range of antiviral host defense genes. In this study, using Irf1 −/− mice, we investigated the role of IRF-1 in modulating pathogenesis of two related arthritogenic alphaviruses, chikungunya virus and Ross River virus. Our studies show that IRF-1 controlled alphavirus replication and swelling in joint-associated tissues within days of infection. Detailed histopathological and virological analyses revealed that IRF-1 preferentially restricted CHIKV infection in cells of nonhematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint-associated tissues, which prevented immunopathology.

scholarly journals Ultrastructural demonstration of CD36 in the alpha-granule membrane of human platelets and megakaryocytes

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3034-3044 ◽  
Author(s):  
G Berger ◽  
JP Caen ◽  
MC Berndt ◽  
EM Cramer
Keyword(s):  
Plasma Membrane ◽  
Subcellular Distribution ◽  
Critical Role ◽  
Staining Technique ◽  
Ultrastructural Observation ◽  
Type I ◽  
Cell Content ◽  
Major Band ◽  
Immunogold Staining ◽  
Granule Membrane

Abstract CD36 (glycoprotein [GP] IV) is a membrane GP of 88 kD found on monocytes, endothelial cells, and platelets. It may serve as a receptor for collagen and is also able to bind thrombospondin (TSP), because a monoclonal antibody to CD36 inhibits TSP binding to thrombin-stimulated platelets. In the following study, we investigated the subcellular distribution of CD36 within normal resting platelets, thrombin- stimulated platelets, and in cultured megakaryocytes (MK) by an immunogold staining technique and electron microscopy. We used an affinity-purified monospecific polyclonal antibody showing a single major band of precipitation at 88 kD via immunoblot analysis. In normal platelets, ultrastructural observation detected immunolabeling for CD36, homogeneously distributed along the platelet plasma membrane and in the luminal side of the open canalicular system (OCS). Moreover, some labeling was found around the alpha-granules along the inner face of their limiting membrane. An average of 70% of granules were labeled. The granule-associated pool of CD36 was estimated at approximately 25% of the total cell content. To exclude the possibility of a cross- reaction with GPIIb-IIIa, platelets from a patient with type I Glanzmann's thrombasthenia (which completely lack GPIIb-IIIa) were studied and showed a similar subcellular distribution of CD36, including alpha-granule membrane labeling. In activated platelets, CD36 was shown to be redistributed to the OCS and pseudopods of the plasma membrane. Platelets from a patient with the Gray platelet syndrome expressed CD36 on their plasma membrane, and some immunolabeling was also found within small abnormal alpha-granules. In cultured MK, CD36 immunolabeling was detected in the Golgi saccules, associated vesicles, immature alpha-granules, and demarcation membranes. In conclusion, this study shows the existence of a significant intragranular pool of CD36 in platelets that may play a critical role in the surface expression of alpha-granule TSP during platelet activation.

scholarly journals Identification of actin-, alpha-actinin-, and vinculin-containing plaques at the lateral membrane of epithelial cells.

1986 ◽  
Vol 102 (5) ◽  
pp. 1843-1852 ◽  
Author(s):  
D Drenckhahn ◽  
H Franz
Keyword(s):  
Plasma Membrane ◽  
Cross Sections ◽  
Three Dimensional ◽  
Intercellular Junctions ◽  
Classical Type ◽  
Type I ◽  
Type Ii ◽  
Microscopic Studies ◽  
Prostatic Epithelium ◽  
Human Intestinal Epithelium

In this paper, a new type of spot desmosome-like junction (type II plaque) is described that is scattered along the entire lateral plasma membrane of rat and human intestinal epithelium. Ultrastructurally type II plaques differed from the classical type of epithelial spot desmosome ("macula adherens", further denoted as type I desmosome) by weak electron density of the membrane-associated plaque material, association of the plaques with microfilaments rather than intermediate filaments, and poorly visible material across the intercellular space. Thus, type II plaques resemble cross-sections of the zonula adherens. Immunofluorescence-microscopic studies were done using antibodies to a main protein associated with the plaques of type I desmosomes (desmoplakin I) and to the three major proteins located at the plaques of the zonula adherens (actin, alpha-actinin, and vinculin). Two types of plaques were visualized along the lateral surface of intestinal and prostatic epithelium: (a) the type I desmosomes, which were labeled with anti-desmoplakin but did not bind antibodies to actin, alpha-actinin, and vinculin, and (b) a further set of similarly sized plaques, which bound antibodies to actin, alpha-actinin, and vinculin but were not stained with anti-desmoplakin. Three-dimensional computer reconstruction of serial sections double-labeled with anti-desmoplakin and anti-alpha-actinin further confirmed that both types of plaques are spatially completely separated from each other along the lateral plasma membrane. The computer graphs further revealed that the actin-, alpha-actinin-, and vinculin-containing plaques have the tendency to form clusters, a feature also typical of type II plaques. It is suggested that the type II plaques represent spot desmosome-like intercellular junctions, which, like the zonula adherens, appear to be linked to the actin filament system. As the type II plaques cover a considerable part of the lateral cell surface, they might play a particular role in controlling cellular shape and intercellular adhesion.

scholarly journals Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism

2002 ◽  
Vol 16 (3) ◽  
pp. 506-514 ◽  
Author(s):  
Yu Li ◽  
Charles Bolten ◽  
B. Ganesh Bhat ◽  
Jessica Woodring-Dietz ◽  
Suzhen Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Element ◽  
Critical Role ◽  
Cell Types ◽  
Plasma Lipoproteins ◽  
Type I ◽  
Type Ii ◽  
Downstream Target ◽  
X Receptors

Abstract The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRα (hLXRα) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2–4 h. Analysis of the hLXRα promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRα:RXR and LXRβ:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRα:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRα and LXRβ activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRα activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRα gene expression. This would lead to increased hLXRα levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.

Differential expression of IL-1 and TNF receptors in murine macrophages infected with virulent vs. avirulentLegionella pneumophila

2000 ◽  
Vol 46 (10) ◽  
pp. 885-891 ◽  
Author(s):  
Shannon McHugh ◽  
Yoshimasa Yamamoto ◽  
Thomas W Klein ◽  
Herman Friedman
Keyword(s):  
Differential Expression ◽  
Legionella Pneumophila ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Receptor Expression ◽  
Cytokine Receptors ◽  
Type I ◽  
Type Ii ◽  
Receptor Mrna

Infection of macrophages from genetically susceptible A/J mice with Legionella pneumophila induces high levels of various cytokines in serum as well as in cultures of spleen or peritoneal cells from the mice. However, modulation of receptor expression for these cytokines during infection has not been studied in detail, even though these receptors on macrophages have a critical role in inflammatory responses during the infection. In the present study, the differential expression of mRNA for TNF and IL-1 receptors as well as receptor antigens during infection of macrophages with virulent vs. avirulent L. pneumophila was investigated. Mouse thioglycollate-elicited peritoneal macrophages showed by RT-PCR constitutive steady-state levels of mRNA for TNF-type I and -type II receptors as well as IL-1 type I receptor. However, IL-1 type II receptor mRNA was not expressed in thioglycollate-elicited macrophages. Infection of macrophages with virulent bacteria caused an upregulation of IL-1 type I and TNF type I receptor mRNA, but had no effect on TNF type II receptor message. Avirulent L. pneumophila infection caused much less induction of these receptor mRNAs. The amount of receptor antigen of IL-1 type I on the surface of macrophages was also increased by infection with virulent L. pneumophila determined by flow cytometric analysis. These results indicate that L. pneumophila infection not only causes induction of various cytokines, but also modulation of certain cytokine receptors, which may regulate the susceptibility to infection.Key words: Legionella pneumophila, cytokine receptors, macrophages.

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