The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Ana I Kuehne - One of the best experts on this subject based on the ideXlab platform.
-
lassa virus entry requires a trigger induced Receptor switch
Science, 2014Co-Authors: Matthijs Raaben, Andrew S Herbert, Ana I Kuehne, Ariel S Wirchnianski, Sarah H Stubbs, Markus Damme, Hans Janssen, Paul Saftig, Sean P J WhelanAbstract:Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface Receptor α-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an Intracellular Receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this Receptor switch in vivo.
-
Ebola virus entry requires the host-programmed recognition of an Intracellular Receptor
The EMBO Journal, 2012Co-Authors: Emily Happy Miller, Gregor Obernosterer, Anuja Krishnan, Esther Ndungo, Rohini G. Sandesara, Matthijs Raaben, Andrew S Herbert, Maika S. Deffieu, Jan E. Carette, Ana I KuehneAbstract:Ebola and Marburg filoviruses cause deadly outbreaks of haemorrhagic fever. Despite considerable efforts, no essential cellular Receptors for filovirus entry have been identified. We showed previously that Niemann-Pick C1 (NPC1), a lysosomal cholesterol transporter, is required for filovirus entry. Here, we demonstrate that NPC1 is a critical filovirus Receptor. Human NPC1 fulfills a cardinal property of viral Receptors: it confers susceptibility to filovirus infection when expressed in non-permissive reptilian cells. The second luminal domain of NPC1 binds directly and specifically to the viral glycoprotein, GP, and a synthetic single-pass membrane protein containing this domain has viral Receptor activity. Purified NPC1 binds only to a cleaved form of GP that is generated within cells during entry, and only viruses containing cleaved GP can utilize a Receptor retargeted to the cell surface. Our findings support a model in which GP cleavage by endosomal cysteine proteases unmasks the binding site for NPC1, and GP–NPC1 engagement within lysosomes promotes a late step in entry proximal to viral escape into the host cytoplasm. NPC1 is the first known viral Receptor that recognizes its ligand within an Intracellular compartment and not at the plasma membrane.
Matthijs Raaben - One of the best experts on this subject based on the ideXlab platform.
-
lassa virus entry requires a trigger induced Receptor switch
Science, 2014Co-Authors: Matthijs Raaben, Andrew S Herbert, Ana I Kuehne, Ariel S Wirchnianski, Sarah H Stubbs, Markus Damme, Hans Janssen, Paul Saftig, Sean P J WhelanAbstract:Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface Receptor α-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an Intracellular Receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this Receptor switch in vivo.
-
Ebola virus entry requires the host-programmed recognition of an Intracellular Receptor
The EMBO Journal, 2012Co-Authors: Emily Happy Miller, Gregor Obernosterer, Anuja Krishnan, Esther Ndungo, Rohini G. Sandesara, Matthijs Raaben, Andrew S Herbert, Maika S. Deffieu, Jan E. Carette, Ana I KuehneAbstract:Ebola and Marburg filoviruses cause deadly outbreaks of haemorrhagic fever. Despite considerable efforts, no essential cellular Receptors for filovirus entry have been identified. We showed previously that Niemann-Pick C1 (NPC1), a lysosomal cholesterol transporter, is required for filovirus entry. Here, we demonstrate that NPC1 is a critical filovirus Receptor. Human NPC1 fulfills a cardinal property of viral Receptors: it confers susceptibility to filovirus infection when expressed in non-permissive reptilian cells. The second luminal domain of NPC1 binds directly and specifically to the viral glycoprotein, GP, and a synthetic single-pass membrane protein containing this domain has viral Receptor activity. Purified NPC1 binds only to a cleaved form of GP that is generated within cells during entry, and only viruses containing cleaved GP can utilize a Receptor retargeted to the cell surface. Our findings support a model in which GP cleavage by endosomal cysteine proteases unmasks the binding site for NPC1, and GP–NPC1 engagement within lysosomes promotes a late step in entry proximal to viral escape into the host cytoplasm. NPC1 is the first known viral Receptor that recognizes its ligand within an Intracellular compartment and not at the plasma membrane.
Daria Mochly-rosen - One of the best experts on this subject based on the ideXlab platform.
-
Cloning of an Intracellular Receptor for protein kinase C: a homolog of the beta subunit of G proteins.
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Dorit Ron, Che-hong Chen, Jeremy S. Caldwell, Lee Jamieson, Elisha Orr, Daria Mochly-rosenAbstract:Abstract Protein kinase C (PKC) translocates from the soluble to the cell particulate fraction on activation. Intracellular Receptors that bind activated PKC in the particulate fraction have been implicated by a number of studies. Previous work identified 30- to 36-kDa proteins in the particulate fraction of heart and brain that bound activated PKC in a specific and saturable manner. These proteins were termed Receptors for activated C-kinase, or RACKs. In the following study, we describe the cloning of a cDNA encoding a 36-kDa protein (RACK1) that fulfills the criteria for RACKs. (i) RACK1 bound PKC in the presence of PKC activators, but not in their absence. (ii) PKC binding to the recombinant RACK1 was not inhibited by a pseudosubstrate peptide or by a substrate peptide derived from the pseudosubstrate sequence, indicating that the binding did not reflect simply PKC association with its substrate. (iii) Binding of PKC to RACK1 was saturable and specific; two other protein kinases did not bind to RACK1. (iv) RACK1 contains two short sequences homologous to a PKC binding sequence previously identified in annexin I and in the brain PKC inhibitor KCIP. Peptides derived from these sequences inhibited PKC binding to RACK1. Finally, RACK1 is a homolog of the beta subunit of G proteins, which were recently implicated in membrane anchorage of the beta-adrenergic Receptor kinase [Pitcher, J., Inglese, L., Higgins, J. B., Arriza, J. A., Casey, P. J., Kim, C., Benovic, J. L., Kwatra, M. M., Caron, M. G. & Lefkowitz, R. J. (1992) Science 257, 1264-1267]. Our in vitro data suggest a role for RACK1 in PKC-mediated signaling.
-
Intracellular Receptors for activated protein kinase C. Identification of a binding site for the enzyme.
The Journal of biological chemistry, 1991Co-Authors: Daria Mochly-rosen, Hanita Khaner, José A. López, Bradley L. SmithAbstract:Protein kinase C (PKC) isozymes comprise a family of cytosolic enzymes that translocate to different Intracellular sites on activation. We have recently characterized at least two Intracellular Receptor proteins for PKC (termed RACKs for Receptors for activated C-kinase) in the Triton-insoluble material of the particulate fraction from neonatal rat heart. Here, we identify a sequence that appears to resemble the PKC binding site on these RACKs. A peptide (peptide I) with the sequence KGDYEKILVALCGGN bound PKC, and binding was markedly increased in the presence of PKC activators. Furthermore, peptide I inhibited PKC binding to RACKs in a dose-dependent manner. These data suggest that these RACKs have a common PKC binding sequence. Since peptide I inhibited PKC binding to RACKs in vitro, it may be a useful tool to inhibit PKC translocation and subsequent function in vivo.
-
Identification of Intracellular Receptor proteins for activated protein kinase C.
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Daria Mochly-rosen, Hanita Khaner, Jamie LopezAbstract:Abstract Protein kinase C (PKC) translocates from the cytosol to the particulate fraction on activation. This activation-induced translocation of PKC is thought to reflect PKC binding to the membrane lipids. However, immunological and biochemical data suggest that PKC may bind to proteins in the cytoskeletal elements in the particulate fraction and in the nuclei. Here we describe evidence for the presence of Intracellular Receptor proteins that bind activated PKC. Several proteins from the detergent-insoluble material of the particulate fraction bound PKC in the presence of phosphatidylserine and calcium; binding was further increased with the addition of diacylglycerol. Binding of PKC to two of these proteins was concentration-dependent, saturable, and specific, suggesting that these binding proteins are Receptors for activated C-kinase, termed here "RACKs." PKC binds to RACKs via a site on PKC distinct from the substrate binding site. We suggest that binding to RACKs may play a role in activation-induced translocation of PKC.
Hiroyuki Arai - One of the best experts on this subject based on the ideXlab platform.
-
identification of an Intracellular Receptor for lysophosphatidic acid lpa lpa is a transcellular pparγ agonist
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Thomas M Mcintyre, Aaron V Pontsler, Adriana R Silva, Andy St Hilaire, Yong Xu, Jerald C Hinshaw, Guy A Zimmerman, Kotaro Hama, Junken Aoki, Hiroyuki AraiAbstract:Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated LPAx Receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated Receptor γ (PPARγ) as an Intracellular Receptor for LPA. The transcription factor PPARγ is activated by several lipid ligands, but agonists derived from physiologic signaling pathways are unknown. We show that LPA, but not its precursor phosphatidic acid, displaces the drug rosiglitazone from the ligand-binding pocket of PPARγ. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPARγ-controlled gene CD36, and induced monocyte lipid accumulation from oxidized low-density lipoprotein via the CD36 scavenger Receptor. The synthetic LPA analogs were effective PPARγ agonists, but were poor ones for LPA1, LPA2, or LPA3 Receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPAx Receptors, show that LPA directly activates PPARγ. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPARγ function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPARγ ligand, placing PPARγ in a signaling pathway, and PPARγ is the first Intracellular Receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPARγ in nucleated cells.
Emily Happy Miller - One of the best experts on this subject based on the ideXlab platform.
-
Ebola virus entry requires the host-programmed recognition of an Intracellular Receptor
The EMBO Journal, 2012Co-Authors: Emily Happy Miller, Gregor Obernosterer, Anuja Krishnan, Esther Ndungo, Rohini G. Sandesara, Matthijs Raaben, Andrew S Herbert, Maika S. Deffieu, Jan E. Carette, Ana I KuehneAbstract:Ebola and Marburg filoviruses cause deadly outbreaks of haemorrhagic fever. Despite considerable efforts, no essential cellular Receptors for filovirus entry have been identified. We showed previously that Niemann-Pick C1 (NPC1), a lysosomal cholesterol transporter, is required for filovirus entry. Here, we demonstrate that NPC1 is a critical filovirus Receptor. Human NPC1 fulfills a cardinal property of viral Receptors: it confers susceptibility to filovirus infection when expressed in non-permissive reptilian cells. The second luminal domain of NPC1 binds directly and specifically to the viral glycoprotein, GP, and a synthetic single-pass membrane protein containing this domain has viral Receptor activity. Purified NPC1 binds only to a cleaved form of GP that is generated within cells during entry, and only viruses containing cleaved GP can utilize a Receptor retargeted to the cell surface. Our findings support a model in which GP cleavage by endosomal cysteine proteases unmasks the binding site for NPC1, and GP–NPC1 engagement within lysosomes promotes a late step in entry proximal to viral escape into the host cytoplasm. NPC1 is the first known viral Receptor that recognizes its ligand within an Intracellular compartment and not at the plasma membrane.
