The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling

Best, Sonja M.

doi:10.1128/jvi.01970-16

Cited by 201 publications

(165 citation statements)

References 108 publications

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“…However, it is not fully understood how evolution in different reservoir hosts to avoid innate immunity has shaped replication and pathogenesis of different flaviviruses following infection of humans. Host-specific interactions with the interferon (IFN) response have been demonstrated for DENV and ZIKV that can only antagonize IFN-dependent signaling in the context of primate hosts 6 . However, the IFN-stimulated genes (IGSs) that might also contribute to host-specific restriction of flaviviruses are not well characterized.…”

Section: Mainmentioning

confidence: 99%

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Chiramel

Meyerson

McNally

et al. 2019

Preprint

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33Tripartite motif-containing protein 5a (TRIM5a) functions as a cellular antiviral restriction 34 factor with exquisite specificity towards the capsid lattices of retroviruses. The relative avidity 35 of TRIM5a binding to retrovirus capsids directly impacts primate species susceptibility to 36 infection, but the antiviral role of TRIM5a is thought limited to retroviruses. In contrast to this 37 current understanding, here we show that both human and rhesus TRIM5a possess potent 38 antiviral function against specific flaviviruses through interaction with the viral protease 39 (NS2B/3) to inhibit virus replication. Importantly, TRIM5a was essential for the antiviral 40 function of IFN-I against sensitive flaviviruses in human cells. However, TRIM5a was ineffective 41 against mosquito-borne flaviviruses (yellow fever, dengue, and Zika viruses) that establish 42 transmission cycles in humans following emergence from non-human primates. Thus, TRIM5a 43 is revealed to possess remarkable plasticity in recognition of diverse virus families, with 44 potential to influence human susceptibility to emerging flaviviruses of global concern. 45 46 47 Main 48Flaviviruses (family Flaviviridae) include 53 recognized virus species of which 40 are known to 49 cause disease in humans, with over 40% of the world's population at risk of flavivirus infection 50 annually 1 . These viruses have high potential for emergence into human populations as 51 witnessed historically through global emergence of dengue virus (DENV), West Nile virus 52 (WNV), and Zika virus (ZIKV). Additional (re)emerging viruses of considerable medical 53 importance include yellow fever virus (YFV), Japanese encephalitis virus (JEV) and members of 54 the tick-borne encephalitis virus (TBEV) serogroup. Flaviviruses share in common a positive-55 sense single-stranded RNA (ssRNA) genome encoding a single polyprotein that is cleaved by 56 host cell signalases 2 and the viral protease to generate three structural (capsid [C], pre-57 membrane [M] and envelope [E]) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, 58NS4A, NS4B and NS5) 3 . Two of the nonstructural proteins have enzymatic activity; the NS3 59 protein encodes the viral RNA helicase and together with its co-factor NS2B (NS2B/3) functions 60

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Section: Mainmentioning

confidence: 99%

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Chiramel

Meyerson

McNally

et al. 2019

Preprint

Self Cite

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“…The MTase domain possesses RNA guanylyltransferase and methyltransferase activities needed for 5′-RNA capping and cap methylations [126,127], whereas the RdRp domain of NS5 is used for the replication of viral genome and carries out both (−) and (+) strand RNA synthesis [128,129]. Furthermore, NS5 antagonizes the host type I interferon response by preventing JAK-STAT signaling and prevents the establishment of cellular antiviral state by blocking the interferon-α/β signaling pathway [130].…”

Section: Intrinsic Disorder and Functionality Of Mature Alkv Proteinsmentioning

confidence: 99%

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

Redwan

Aljaddawi

Uversky

2018

Cell. Mol. Life Sci.

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Infection by the Alkhurma virus (ALKV) leading to the Alkhurma hemorrhagic fever is a common thread in Saudi Arabia, with no efficient treatment or prevention available as of yet. Although the rational drug design traditionally uses information on known 3D structures of viral proteins, intrinsically disordered proteins (i.e., functional proteins that do not possess unique 3D structures), with their multitude of disorder-dependent functions, are crucial for the biology of viruses. Here, viruses utilize disordered regions in their invasion of the host organisms and in hijacking and repurposing of different host systems. Furthermore, the ability of viruses to efficiently adjust and accommodate to their hostile habitats is also intrinsic disorderdependent. However, little is currently known on the level of penetrance and functional utilization of intrinsic disorder in the ALKV proteome. To fill this gap, we used here multiple computational tools to evaluate the abundance of intrinsic disorder in the ALKV genome polyprotein. We also analyzed the peculiarities of intrinsic disorder predisposition of the individual viral proteins, as well as human proteins known to be engaged in interaction with the ALKV proteins. Special attention was paid to finding a correlation between protein functionality and structural disorder. To the best of our knowledge, this work represents the first systematic study of the intrinsic disorder status of ALKV proteome and interactome.Electronic supplementary material The online version of this article (https ://doi.

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“…Flavivirus subversion of the type I interferon (IFN) pathway is well described (11,12) and includes reports of degradation of STAT2 and subsequent reduction of IFN signaling during ZIKV infection of human cells (13)(14)(15)(16). The relationship between ZIKV and the oligoadenylate synthetase-RNase L (OAS-RNase L) pathway has yet to be investigated, although there are reports of other flaviviruses sensitive to this pathway (17,18).…”

mentioning

confidence: 99%

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Whelan

Silverman

et al. 2019

J Virol

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There is currently no knowledge of how the emerging human pathogen Zika virus (ZIKV) interacts with the antiviral endoribonuclease L (RNase L) pathway during infection. Since activation of RNase L during infection typically limits virus production dramatically, we used CRISPR-Cas9 gene editing technology to knockout (KO) targeted host genes involved in the RNase L pathway to evaluate the effects of RNase L on ZIKV infection in human A549 cells. RNase L was activated in response to ZIKV infection, which degraded ZIKV genomic RNA. Surprisingly, despite viral genome reduction, RNase L activity did not reduce ZIKV infectious titers. In contrast, both the flavivirus dengue virus and the alphavirus Sindbis virus replicated to significantly higher titers in RNase L KO cells compared to wild-type (WT) cells. Using MAVS/RNase L double KO cells, we demonstrated that the absence of increased ZIKV production in RNase L KO cells was not due to compensation by enhanced type I interferon transcripts to thus inhibit virus production. Finally, when synthetic doublestranded RNA was detected by OAS3 to induce RNase L antiviral activity prior to ZIKV infection, we observed reduced ZIKV replication factory formation, as well as a 42-fold reduction in virus yield in WT but not RNase L KO cells. This study proposes that ZIKV evades RNase L antiviral activity by generating a viral genome reservoir protected from RNase L cleavage during early infection, allowing for sufficient virus production before RNase L activation is detectable.

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The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling

Cited by 201 publications

References 108 publications

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

Zika Virus Production Is Resistant to RNase L Antiviral Activity

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