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The ligand preferences of innate immune receptors RIG-I and LGP2

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TitleInfo
Title
The ligand preferences of innate immune receptors RIG-I and LGP2
Name (type = personal)
NamePart (type = family)
Wang
NamePart (type = given)
Chen
DisplayForm
Chen Wang
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Marcotrigiano
NamePart (type = given)
Joseph
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Joseph Marcotrigiano
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Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Arnold
NamePart (type = given)
Eddy
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Eddy Arnold
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Sant'Angelo
NamePart (type = given)
Derek
DisplayForm
Derek Sant'Angelo
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Patel
NamePart (type = given)
Smita
DisplayForm
Smita Patel
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
The innate immunity serves as the first line against pathogen defense. Many receptors and factors play important roles in the innate immune response. A receptor family, retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs) consist of three members, RIG-I, MDA5 and LGP2. RIG-I specifically distinguishes viral RNAs in a diverse cellular RNA environment. When activated by these RNAs, RIG-I triggers downstream pathways and induces innate immune responses such as interferon production to establish an anti-viral state in host cells. Based on previous studies, the 5’ triphosphorylated (5’ppp) blunt-ended RNA bearing a double-strand (ds) panhandle structure at the 5’ end is the ligand for RIG-I. This 5’ triphosphorylation is often seen in viral RNAs. Cellular RNAs, such as messenger RNAs, are usually “capped” at the 5’ end with a 7-methyl guanidine (m7G) via a triphosphate bridge (cap-0). Since the triphosphate is “protected” by the m7G, it was believed that the structural basis of RNA discrimination by RIG-I was the presence of m7G. However, our biochemical, biophysical and cell signaling studies show that RIG-I can recognize dsRNA with cap-0 to a similar extent as 5’ppp dsRNA. Structural data of RIG-I in complex with Cap-0 RNA reveals the ability of RIG-I to accommodate the m7G moiety. In contrast, dsRNA with m7G and an additional 2’-O-methyl group on the 5’ end nucleotide ribose (cap-1) does not stimulate RIG-I and abrogates RIG-I signaling through a mechanism involving residue His830. This histidine is critical for RNA discrimination by RIG-I. Unlike RIG-I, the role of the innate immune receptor LGP2 is not well understood. Lacking domains for signaling, LGP2 is believed to be a regulator of RIG-I and MDA5. Characteristics of nucleic acid binding by LGP2 are not understood, and its relationship with RIG-I needs further studies. Our biochemical studies of LGP2 show higher ATP turnover rate in the presence of 5’OH dsRNA than viral RNA mimics, and the binding affinity of LGP2 with 5’OH dsRNA is relatively tight. 5’OH dsRNA has been shown to activate RIG-I, indicating an overlap in ligands between LGP2 and RIG-I. Competition assays show 5’OH dsRNA preferentially interacts with LGP2, suggesting a mechanism in which LGP2 sequesters non-PAMP ligand of RIG-I to diminish misactivations. Overall, the studies provide further understanding of the early steps in the anti-viral process from the activation stage, which could aid in vaccine development and the design of compound agonist to complement approaches for developing RLR based therapeutics.
Subject (authority = RUETD)
Topic
Microbiology and Molecular Genetics
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8687
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xiii, 108 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Ligands
Subject (authority = ETD-LCSH)
Topic
Natural immunity
Note (type = statement of responsibility)
by Chen Wang
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3VT1WJF
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Wang
GivenName
Chen
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-02-07 11:32:22
AssociatedEntity
Name
Chen Wang
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2018-02-19T20:56:57
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-02-19T20:56:57
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