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Hybrid structural biology studies reveal a novel mechanism by which influenza B NS1 protein suppresses host innate immune response

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Title
Hybrid structural biology studies reveal a novel mechanism by which influenza B NS1 protein suppresses host innate immune response
Name (type = personal)
NamePart (type = family)
Woltz
NamePart (type = given)
Ryan
NamePart (type = date)
1986-
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Ryan Woltz
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Montelione
NamePart (type = given)
Gaetano T.
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Gaetano T. Montelione
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Advisory Committee
Role
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chair
Name (type = personal)
NamePart (type = family)
Arnold
NamePart (type = given)
Eddy
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Eddy Arnold
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Advisory Committee
Role
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internal member
Name (type = personal)
NamePart (type = family)
Khare
NamePart (type = given)
Sagar
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Sagar Khare
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Roth
NamePart (type = given)
Monica
DisplayForm
Monica Roth
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
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school
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Text
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theses
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2019
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2019-05
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2019
Language
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English
Abstract
Influenza is a highly contagious respiratory disease, which can have severe impacts on human health. Influenza type B is traditionally known as the seasonal flu and is the main source for annually occurring influenza outbreaks. The Non-Structural protein 1 of influenza B (NS1B) is a highly conserved protein that the influenza virus produces post infection. NS1B is hypothesized to inhibit the innate immune system via interactions with the RIG-I activation pathway. NS1B has been known to bind dsRNA via its N-terminal domain (NS1B-NTD) for decades, but recently a second RNA binding site was discovered on the C-terminal domain of NS1B (NS1B-CTD). Due to the high conservation of NS1B, its ability to inhibit the innate immune system, and the recent discovery of a second RNA binding domain, this dissertation research focused on the biological function of this second RNA binding site. We discovered a surprising novel blunt-end binding orientation of the NS1B-CTD by dsRNA. We then looked at the connection between RIG-I’s well-known ability to detect and bind triphosphorylated-5’ hairpin RNA (3P-5’-hpRNA) with a much higher affinity than OH-5’ hairpin RNA (OH-5’ hpRNA). We discovered similar binding affinity changes and characteristics with NS1BCTD and the 3P-5’-hpRNA/OH-5’ hpRNA. When the second RNA binding site in NS1B was mutated in transgenic influenza B viruses, we observed reduction in the ability of the virus to suppress Rig-I activation, as Rig-I induced phosphorylation of IRF3 was no longer suppressed flowing virus infection. Our results suggests that the function of the second RNA binding site in the CTD of wildtype NS1B is to outcompete RIG-I for its RNA substrates, typically 5’ triphosphorylaed vRNA molecules. Based on these studies we propose that NS1B-CTD acts as a sensory domain with high specificity for vRNA molecules, which form a “panhandle dsRNA duplex structure” with a unique 3P-5’ modification not found in host cells. This interaction functions to prevent activation of Rig-I, and the innate host immune response.
Subject (authority = ETD-LCSH)
Topic
Influenza -- Research
Subject (authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject (authority = ETD-LCSH)
Topic
RNA-protein interactions
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9825
PhysicalDescription
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application/pdf
InternetMediaType
text/xml
Extent
1 online resource (viii, 171 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Immune response
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-29bz-pv20
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Woltz
GivenName
Ryan
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-04-12 12:42:53
AssociatedEntity
Name
Ryan Woltz
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Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
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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.
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Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-05-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2019-06-17T20:40:40
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1.7
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