Systems Biology Reveals NS4B-Cyclophilin A Interaction: A New Target to Inhibit YFV Replication

Vidotto, Alessandra; Morais, Ana Theresa Silveira de; Ribeiro, Milene Rocha; Pacca, Carolina Colombelli; Terzian, Ana Carolina Bernardes; Gil, Laura Helena Vega Gonzales; Mohana‐Borges, Ronaldo; Gallay, Philippe; Nogueira, Maurício Lacerda

doi:10.1021/acs.jproteome.6b00933

Cited by 17 publications

(24 citation statements)

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“…The latter study showed an essential role of CypA's PPIase activity in DENV and WNV replication. In the case of WNV and Japanese encephalitis virus (JEV), the inhibitory effect of CsA was attributed to blocking a functional CypA-NS5 interaction (Qing et al, 2009), while CypA was shown to interact with NS4B during YFV infection (Vidotto et al, 2017). Interestingly, JEV seems to depend mainly on enzymatically active CypB for its replication, mostly via an interaction with NS4A (Kambara et al, 2011).…”

Section: Flavivirusesmentioning

confidence: 99%

Cyclophilins and cyclophilin inhibitors in nidovirus replication

et al. 2018

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Cyclophilins (Cyps) belong to the family of peptidyl-prolyl isomerases (PPIases). The PPIase activity of most Cyps is inhibited by the immunosuppressive drug cyclosporin A and several of its non-immunosuppressive analogs, which can also block the replication of nidoviruses (arteriviruses and coronaviruses). Cyclophilins have been reported to play an essential role in the replication of several other RNA viruses, including human immunodeficiency virus-1, hepatitis C virus, and influenza A virus. Likewise, the replication of various nidoviruses was reported to depend on Cyps or other PPIases. This review summarizes our current understanding of this class of nidovirus-host interactions, including the potential function of in particular CypA and the inhibitory effect of Cyp inhibitors. Also the involvement of the FK-506-binding proteins and parvulins is discussed. The nidovirus data are placed in a broader perspective by summarizing the most relevant data on Cyp interactions and Cyp inhibitors for other RNA viruses.

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Section: Flavivirusesmentioning

confidence: 99%

Cyclophilins and cyclophilin inhibitors in nidovirus replication

et al. 2018

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“…6c, d). Thus, although CypA is required for flavivirus replication, and binds to nonstructural proteins NS5 36 and NS4B 37 within viral replication complexes, TRIM5-CypA fusion proteins are not sufficient to restrict tick-borne flavivirus replication, confirming the importance of the B30.2/SPRY domain of TRIM5α in flavivirus restriction.…”

Section: Resultsmentioning

confidence: 98%

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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“…Apesar das extensas procuras por antivirais, ainda não existe um tratamento específico para febre amarela. Atualmente, o tratamento é feito apenas para suporte e inclui analgésicos, antitérmicos e antieméticos [24][25][26][27][28] .…”

Section: Patogenia Diagnóstico E Tratamentounclassified