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Dissecting the Novel Roles of TRIM56...

Liu, Baoming.

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Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity./
作者:	Liu, Baoming.
面頁冊數:	104 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.
Contained By:	Dissertation Abstracts International77-08B(E).
標題:	Virology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10094589
ISBN:	9781339599045

Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity.
Liu, Baoming.

Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity. - 104 p.

Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.

Thesis (Ph.D.)--The University of Tennessee Health Science Center, 2016.

The tripartite motif-containing (TRIM) proteins have emerged as a new class of host antiviral restriction factors, with several demonstrating roles in regulating innate antiviral responses. Of >70 known TRIMs, TRIM56 inhibits replication of bovine viral diarrhea virus, a ruminant pestivirus of the family Flaviviridae, but has no appreciable effect on VSV, a rhabdovirus. We have also shown that TRIM56 forms a complex with the Toll-like receptor-3 (TLR3) adaptor, TRIF, via its C-terminal residues 621-750, and augments TLR3-mediated interferon (IFN) induction and establishment of an antiviral state. Yet, TRIM56's antiviral spectrum and the precise underlying mechanisms by which TRIM56 executes its direct antiviral functions and modulates TLR3 signaling remain undefined. Also unclear are the molecular determinants governing the direct and indirect antiviral activities of TRIM56.

ISBN: 9781339599045Subjects--Topical Terms:

642304
Virology.

Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity.
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245 1 0 $a Dissecting the Novel Roles of TRIM56 in Antiviral Innate Immunity.
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502 $a Thesis (Ph.D.)--The University of Tennessee Health Science Center, 2016.
520 $a The tripartite motif-containing (TRIM) proteins have emerged as a new class of host antiviral restriction factors, with several demonstrating roles in regulating innate antiviral responses. Of >70 known TRIMs, TRIM56 inhibits replication of bovine viral diarrhea virus, a ruminant pestivirus of the family Flaviviridae, but has no appreciable effect on VSV, a rhabdovirus. We have also shown that TRIM56 forms a complex with the Toll-like receptor-3 (TLR3) adaptor, TRIF, via its C-terminal residues 621-750, and augments TLR3-mediated interferon (IFN) induction and establishment of an antiviral state. Yet, TRIM56's antiviral spectrum and the precise underlying mechanisms by which TRIM56 executes its direct antiviral functions and modulates TLR3 signaling remain undefined. Also unclear are the molecular determinants governing the direct and indirect antiviral activities of TRIM56.
520 $a Herein, in Chapter 3, I show that TRIM56 poses a barrier to infections by yellow fever virus (YFV), dengue virus serotype-2 (DENV2), and human coronavirus virus (HCoV)-OC43. Moreover, I demonstrate that TRIM56's anti-flavivirus effects required both the E3 ligase activity that lies in the N-terminal RING domain and the integrity of its C-terminal portion, while the restriction of HCoV-OC43 relied upon the TRIM56 E3 ligase activity alone. Furthermore, TRIM56 was revealed to impair YFV and DENV2 propagation by suppressing intracellular viral RNA accumulation but to compromise HCoV-OC43 infection at a later step in the viral life cycle, suggesting that distinct TRIM56 domains accommodate differing antiviral mechanisms. Next, in Chapter 4, I show TRIM56 puts a check on replication of influenza A and B viruses in cell culture. Interestingly, the anti-influenza activity was independent of the E3 ligase activity, B-box, or coiled-coil domains. Rather, deletion of a 63-residue long, C-terminal tail portion of TRIM56 abrogated the antiviral function. Moreover, expression of this short C-terminal segment curtailed the replication of influenza viruses as effectively as that of full-length TRIM56. Mechanistically, TRIM56 was found to specifically impede intracellular influenza virus RNA synthesis. Altogether, TRIM56 is a versatile antiviral host factor that confers resistance to YFV, DENV2, HCoV-OC43 and influenza viruses through overlapping and distinct molecular determinants. Last, in Chapter 5, I report TRIM56 over-expression promoted activation of NF-kappaB following TLR3 engagement but not that induced by TNF-alpha- or IL-1beta. Next, I observed that the coiled-coil domain and residues 431-610, but not the B-box or residues 355-433, were required for TRIM56 augmentation of TLR3-dependent IFN-beta promoter activation. Furthermore, alanine screening mutagenesis suggested the S469A+S471A+S475A triple mutant and S471A, S475A and S710A single mutant failed to enhance TLR3 signaling. In line with this, S471A, S475A and S710A, as well as the coiled-coil deletion mutant lost the ability to enhance poly-I:C-mediated establishment of an antiviral state compared with wild-type TRIM56. Collectively, these data reveal novel insights into the mechanism of TRIM56 augmentation of TLR3-dependent antiviral response and highlight a role for TRIM56 scaffolding and phosphorylation in positive regulation of TLR3 signaling.
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