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Document Type:Latin Dissertation
Language of Document:English
Record Number:54183
Doc. No:TL24137
Call number:‭3165009‬
Main Entry:Jason J. Rodriguez
Title & Author:Molecular mechanism of interferon evasion by Henipavirus V proteinsJason J. Rodriguez
College:Mount Sinai School of Medicine of New York University
Date:2005
Degree:Ph.D.
student score:2005
Page No:171
Abstract:Interferons (IFNs) are extracellular polypeptides that mediate innate and adaptive antiviral immunity in mammalian cells. Secreted from cells, IFNs bind to transmembrane receptors on neighboring cells to activate the intracellular JAK-STAT signaling cascade. Signaling by type I IFN (IFNα/β) activates the IFN stimulated gene factor 3 (ISGF3) transcription factor complex comprised of signal transducer and activator of transcription (STAT) 1, STAT2, and a member of the interferon regulatory factor (IRF) family, IRF9. Type II IFN (IFNγ) signaling activates the gamma activated factor (GAF) transcription factor complex, which is composed of STAT1 homodimers. In both cases, these transcription factor complexes rapidly translocate to the nucleus and initiate expression of IFN-stimulated genes (ISGs) whose gene products include many antiviral effectors. IFN stimulation establishes a broadly effective antiviral state that inhibits diverse virus replication strategies. Viruses have evolved diverse methods to inhibit IFN signaling and avoid host antiviral responses. Members of the Paramyxoviridae family of RNA viruses evade the IFN response by directly targeting STAT proteins. The paramyxovirus STAT targeting activity can be attributed to a virus encoded protein, called V. The V protein is encoded within a polycistronic gene and contains a highly conserved zinc-binding cysteine-rich C-terminal domain (CTD). Two recently emergent paramyxoviruses of the Henipavirus genus, Hendra virus and Nipah virus, caused fatal respiratory disease and encephalitis among humans and animal livestock in Australia and Malaysia. These two paramyxoviruses (herein collectively referred to as Henipaviruses ) also encode V proteins. Results will demonstrate that, similar to other paramyxoviruses, Henipaviruses also block IFN signal transduction by disrupting STAT protein function. The Henipavirus V proteins inhibit both IFNα/β and IFNγ signal transduction by a unique mechanism involving interaction with both STAT1 and STAT2. Due to the action of a nuclear export mechanism, STAT1 and STAT2 are sequestered in high molecular weight cytoplasmic complexes. Results indicate that the Nipah virus V protein prevents IFN signaling in the absence of its nuclear export activity. Instead, a 60 amino acid Nipah V peptide that binds STAT1 is sufficient for inhibition of IFN signaling. A larger Nipah virus V peptide and the presence of cellular STAT1 is required for Nipah virus V to interact with STAT2. These findings reveal targets for rational drug design and could guide the development of Henipavirus therapeutics.
Subject:Health and environmental sciences; Biological sciences; Antiviral; Henipavirus V; Interferon; Paramyxovirus; STAT; Molecular biology; Immunology; 0982:Immunology; 0307:Molecular biology
Added Entry:C. M. Horvath
Added Entry:Mount Sinai School of Medicine of New York University