scholarly journals A Single Amino Acid Determines the Immunostimulatory Activity of Interleukin 10

2000 ◽  
Vol 191 (2) ◽  
pp. 213-224 ◽  
Author(s):  
Yaozhong Ding ◽  
Lihui Qin ◽  
Serguei V. Kotenko ◽  
Sidney Pestka ◽  
Jonathan S. Bromberg
Keyword(s):  
Amino Acid ◽  
Immune Responses ◽  
Cell Types ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Single Amino Acid ◽  
Immunostimulatory Activity ◽  
Barr Virus ◽  
Ligand Interactions ◽  
Epstein Barr

Cellular interleukin 10s (cIL-10s) of human and murine origin have extensive sequence and structural homology to the Epstein-Barr virus BCRF-I gene product, known as viral IL-10 (vIL-10). Although these cytokines share many immunosuppressive properties, vIL-10 lacks several of the immunostimulatory activities of cIL-10 on certain cell types. The molecular and cellular bases for this dichotomy are not currently defined. Here, we show that the single amino acid isoleucine at position 87 of cIL-10 is required for its immunostimulatory function. Substitution of isoleucine in cIL-10 with alanine, which corresponds to the vIL-10 residue, abrogates immunostimulatory activity for thymocytes, mast cells, and alloantigenic responses while preserving immunosuppressive activity for inhibition of interferon γ production and prolongation of cardiac allograft survival. Conversely, substitution of alanine with isoleucine in vIL-10 converts it to a cIL-10–like molecule with immunostimulatory activity. This single conservative residue alteration significantly affects ligand affinity for receptor; however, affinity changes do not necessarily alter specific activities for biologic responses in a predictable fashion. These results suggest complex regulation of IL-10 receptor–ligand interactions and subsequent biological responses. These results demonstrate that vIL-10 may represent a captured and selectively mutated cIL-10 gene that benefits viral pathogenesis by leading to ineffective host immune responses. The ability to manipulate the activity of IL-10 in either a stimulatory or suppressive direction may be of practical value for regulating immune responses for disease therapy, and of theoretical value for determining what aspects of IL-10 activity are important for normal T cell responses.

scholarly journals Orf virus-encoded interleukin-10 stimulates the proliferation of murine mast cells and inhibits cytokine synthesis in murine peritoneal macrophages

2002 ◽  
Vol 83 (5) ◽  
pp. 1049-1058 ◽  
Author(s):  
Wendy Imlach ◽  
Catherine A. McCaughan ◽  
Andrew A. Mercer ◽  
David Haig ◽  
Stephen B. Fleming
Keyword(s):  
Amino Acid ◽  
Mast Cells ◽  
Cell Types ◽  
Interleukin 10 ◽  
Peritoneal Macrophages ◽  
Orf Virus ◽  
Single Amino Acid ◽  
Viral Gene ◽  
Barr Virus ◽  
Polypeptide Structure

Orf virus (ORFV) is the type species of the parapoxvirus genus and produces cutaneous pustular lesions in sheep, goats and humans. The genome encodes a polypeptide with remarkable homology to interleukin-10 (IL-10), particularly ovine IL-10, and also to IL-10-like proteins encoded by Epstein–Barr virus (EBV) and equine herpesvirus. IL-10 is a pleiotropic cytokine that can exert either immunostimulatory or immunosuppressive effects on many cell types. We have expressed and purified C-terminal FLAG and His6-tagged versions of ORFV-IL-10 and shown that ORFV-IL-10 costimulates murine mast cells (MC/9) and inhibits tumour necrosis factor-α synthesis in activated mouse peritoneal macrophages. Our results demonstrate that although ORFV-IL-10 is structurally similar to EBV-IL-10 it has evolved a different spectrum of activities. EBV-IL-10 does not stimulate the proliferation of thymocytes or mast cells whereas ORFV-IL-10 has both of these activities. Recent studies show that the critical difference in molecular structure of human IL-10 and EBV-IL-10, which may be the basis of their functional differences, is linked to a single amino acid substitution. Consistent with the activity spectrum reported here for ORFV-IL-10, the viral gene encodes the critical amino acid seen in human IL-10. Although the ORFV-IL-10 gene has clearly undergone significant evolutionary change at the nucleotide level compared with ovine IL-10, it has largely retained the polypeptide structure and functional characteristics of its ovine counterpart, suggesting that mutations of the gene to a potentially more potent immunosuppressive form may compromise the co-existence of host and virus.

scholarly journals Joint Effects of Epstein-Barr Virus and Polymorphisms in Interleukin-10 and Interferon-γ on Breast Cancer Risk

2011 ◽  
Vol 205 (1) ◽  
pp. 64-71 ◽  
Author(s):  
Jian-Rong He ◽  
Li-Juan Chen ◽  
Yi Su ◽  
Yu-Ling Cen ◽  
Lu-Ying Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Epstein Barr Virus ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Joint Effects ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals A Single Amino Acid in EBNA-2 Determines Superior B Lymphoblastoid Cell Line Growth Maintenance by Epstein-Barr Virus Type 1 EBNA-2

2014 ◽  
Vol 88 (16) ◽  
pp. 8743-8753 ◽  
Author(s):  
S. Tzellos ◽  
P. B. Correia ◽  
C. E. Karstegl ◽  
L. Cancian ◽  
J. Cano-Flanagan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Line ◽  
Virus Type ◽  
Epstein Barr Virus ◽  
Lymphoblastoid Cell Line ◽  
Single Amino Acid ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Mutation of a Single Amino Acid Residue in the Basic Region of the Epstein-Barr Virus (EBV) Lytic Cycle Switch Protein Zta (BZLF1) Prevents Reactivation of EBV from Latency

2005 ◽  
Vol 79 (21) ◽  
pp. 13822-13828 ◽  
Author(s):  
Celine Schelcher ◽  
Sarah Valencia ◽  
Henri-Jacques Delecluse ◽  
Matthew Hicks ◽  
Alison J. Sinclair
Keyword(s):  
Amino Acid ◽  
Epstein Barr Virus ◽  
Cysteine Residue ◽  
Lytic Cycle ◽  
Single Amino Acid ◽  
Barr Virus ◽  
Single Amino Acid Residue ◽  
Independent Functions ◽  
Epstein Barr ◽  
Basic Region

ABSTRACT Zta, the product of the BZLF1 gene carried by Epstein-Barr virus (EBV), is crucial for reactivation of EBV from latency. Zta is a member of the bZIP family of transcription factors, and in common with many of these, Zta possesses a conserved cysteine residue in its basic region (C189) and a further cysteine residue in its ZIP region (C222). We demonstrate that C189 is required to reactivate EBV from latency but C222 is not and that this single amino acid affects two independent functions of Zta, (i) binding to a Zta-responsive site and (ii) manipulating the cell cycle.

scholarly journals Potential Selection of LMP1 Variants in Nasopharyngeal Carcinoma

2004 ◽  
Vol 78 (2) ◽  
pp. 868-881 ◽  
Author(s):  
Rachel H. Edwards ◽  
Diane Sitki-Green ◽  
Dominic T. Moore ◽  
Nancy Raab-Traub
Keyword(s):  
Amino Acid ◽  
Cytotoxic T Lymphocyte ◽  
Amino Acid Sequences ◽  
Barr Virus ◽  
Distinct Sequence ◽  
Epstein Barr ◽  
Virus Latent Membrane Protein ◽  
Multiple Strains ◽  
Carboxy Terminal ◽  
Selection Of

ABSTRACT Seven distinct sequence variants of the Epstein-Barr virus latent membrane protein 1 (LMP1) have been identified by distinguishing amino acid changes in the carboxy-terminal domain. In this study the transmembrane domains are shown to segregate identically with the distinct carboxy-terminal amino acid sequences. Since strains of LMP1 have been shown to differ in abundance between blood and throat washes, nasopharyngeal carcinomas (NPCs) from areas of endemicity and nonendemicity with matching blood were analyzed by using a heteroduplex tracking assay to distinguish LMP1 variants. Striking differences were found between the compartments with the Ch1 strain prevalent in the NPCs from areas of endemicity and nonendemicity and the B958 strain prevalent in the blood of the endemic samples, whereas multiple strains of LMP1 were prevalent in the blood of the nonendemic samples. The possible selection against the B958 strain appearing in the tumor was highly significant (P < 0.0001). Sequence analysis of the full-length LMP1 variants revealed changes in many of the known and computer-predicted HLA-restricted epitopes with changes in key positions in multiple, potential epitopes for the specific HLA of the patients. These amino acid substitutions at key positions in the LMP1 epitopes may result in a reduced cytotoxic-T-lymphocyte response. These data indicate that strains with specific variants of LMP1 are more likely to be found in NPC. The predominance of specific LMP1 variants in NPC could reflect differences in the biologic or molecular properties of the distinct forms of LMP1 or possible immune selection.

OR10 Genetic predisposition to interleukin-10 production influences epstein-barr virus reactivation after renal transplantation

2015 ◽  
Vol 76 ◽  
pp. 21
Author(s):  
Gaurav Tripathi ◽  
Abdulnaser Abadi ◽  
Poonam Dharmani-Khan ◽  
Lee Anne Tibbles ◽  
Serdar Yilmaz ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Genetic Predisposition ◽  
Epstein Barr Virus ◽  
Interleukin 10 ◽  
Virus Reactivation ◽  
Barr Virus ◽  
Epstein Barr ◽  
Epstein Barr Virus Reactivation

scholarly journals Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.

1996 ◽  
Vol 16 (3) ◽  
pp. 952-959 ◽  
Author(s):  
J J Hsieh ◽  
T Henkel ◽  
P Salmon ◽  
E Robey ◽  
M G Peterson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Epstein Barr Virus ◽  
Cell Fate Decisions ◽  
Barr Virus ◽  
Amino Acid Region ◽  
Nuclear Events ◽  
Epstein Barr

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.

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