TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection Through Interaction with the NS3 Protease

Overview

Journal iScience

Publisher Cell Press

Date 2019 May 27

PMID 31129244

Citations 5

Authors

Brian H Youseff

Thomas G Brewer

Kristin L McNally

Adaeze O Izuogu

Kirk J Lubick

John B Presloid

Saad Alqahtani

Saurabh Chattopadhyay

Sonja M Best

Xiche Hu

R Travis Taylor

Affiliations

Soon will be listed here.

Abstract

Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

Citing Articles

ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.

Zhang S, Luo C, Chen Q, Li N, Liao X, Wu J iScience. 2024; 27(9):110757.

PMID: 39280623 PMC: 11401155. DOI: 10.1016/j.isci.2024.110757.

Transcriptional Response to Tick-Borne Flavivirus Infection in Neurons, Astrocytes and Microglia In Vivo and In Vitro.

Rosendal E, Lindqvist R, Chotiwan N, Henriksson J, Overby A Viruses. 2024; 16(8).

PMID: 39205301 PMC: 11359927. DOI: 10.3390/v16081327.

Enhanced NF-κB activation via HIV-1 Tat-TRAF6 cross-talk.

Li Y, Liu X, Fujinaga K, Gross J, Frankel A Sci Adv. 2024; 10(3):eadi4162.

PMID: 38241362 PMC: 10798561. DOI: 10.1126/sciadv.adi4162.

Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation.

Latanova A, Starodubova E, Karpov V Viruses. 2022; 14(8).

PMID: 36016430 PMC: 9414172. DOI: 10.3390/v14081808.

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication.

Glanz A, Chawla K, Fabry S, Subramanian G, Garcia J, Jay B Viruses. 2020; 12(4).

PMID: 32295140 PMC: 7232324. DOI: 10.3390/v12040442.

References

Leyssen P, De Clercq E, Neyts J . Perspectives for the treatment of infections with Flaviviridae. Clin Microbiol Rev. 2000; 13(1):67-82, table of contents. PMC: 88934. DOI: 10.1128/CMR.13.1.67. View

Tautz N, Kaiser A, Thiel H . NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions. Virology. 2000; 273(2):351-63. DOI: 10.1006/viro.2000.0425. View

Hanley K, Lee J, Blaney Jr J, Murphy B, Whitehead S . Paired charge-to-alanine mutagenesis of dengue virus type 4 NS5 generates mutants with temperature-sensitive, host range, and mouse attenuation phenotypes. J Virol. 2001; 76(2):525-31. PMC: 136841. DOI: 10.1128/jvi.76.2.525-531.2002. View

Ye H, Arron J, Lamothe B, Cirilli M, Kobayashi T, Shevde N . Distinct molecular mechanism for initiating TRAF6 signalling. Nature. 2002; 418(6896):443-7. DOI: 10.1038/nature00888. View

Blaney Jr J, Johnson D, Manipon G, Firestone C, Hanson C, Murphy B . Genetic basis of attenuation of dengue virus type 4 small plaque mutants with restricted replication in suckling mice and in SCID mice transplanted with human liver cells. Virology. 2002; 300(1):125-39. DOI: 10.1006/viro.2002.1528. View

Wu H, Arron J . TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays. 2003; 25(11):1096-105. DOI: 10.1002/bies.10352. View

Mao L, Wang Y, Liu Y, Hu X . Multiple intermolecular interaction modes of positively charged residues with adenine in ATP-binding proteins. J Am Chem Soc. 2003; 125(47):14216-7. DOI: 10.1021/ja036096p. View

Gentry J, Rutkoski N, Burke T, Carter B . A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF. J Biol Chem. 2004; 279(16):16646-56. DOI: 10.1074/jbc.M309209200. View

Chambers T, Droll D, Tang Y, Liang Y, Ganesh V, Murthy K . Yellow fever virus NS2B-NS3 protease: characterization of charged-to-alanine mutant and revertant viruses and analysis of polyprotein-cleavage activities. J Gen Virol. 2005; 86(Pt 5):1403-1413. DOI: 10.1099/vir.0.80427-0. View

10.

Best S, Morris K, Shannon J, Robertson S, Mitzel D, Park G . Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol. 2005; 79(20):12828-39. PMC: 1235813. DOI: 10.1128/JVI.79.20.12828-12839.2005. View

11.

Rumyantsev A, Murphy B, Pletnev A . A tick-borne Langat virus mutant that is temperature sensitive and host range restricted in neuroblastoma cells and lacks neuroinvasiveness for immunodeficient mice. J Virol. 2006; 80(3):1427-39. PMC: 1346960. DOI: 10.1128/JVI.80.3.1427-1439.2006. View

12.

Erbel P, Schiering N, DArcy A, Renatus M, Kroemer M, Pheng Lim S . Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol. 2006; 13(4):372-3. DOI: 10.1038/nsmb1073. View

13.

Pastorino B, Peyrefitte C, Grandadam M, Thill M, Tolou H, Bessaud M . Mutagenesis analysis of the NS2B determinants of the Alkhurma virus NS2B-NS3 protease activation. J Gen Virol. 2006; 87(Pt 11):3279-3283. DOI: 10.1099/vir.0.82088-0. View

14.

Noels H, van Loo G, Hagens S, Broeckx V, Beyaert R, Marynen P . A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2middle dotMALT1 fusions. J Biol Chem. 2007; 282(14):10180-9. DOI: 10.1074/jbc.M611038200. View

15.

Bera A, Kuhn R, Smith J . Functional characterization of cis and trans activity of the Flavivirus NS2B-NS3 protease. J Biol Chem. 2007; 282(17):12883-92. DOI: 10.1074/jbc.M611318200. View

16.

Inoue J, Gohda J, Akiyama T . Characteristics and biological functions of TRAF6. Adv Exp Med Biol. 2007; 597:72-9. DOI: 10.1007/978-0-387-70630-6_6. View

17.

Chung J, Lu M, Yin Q, Lin S, Wu H . Molecular basis for the unique specificity of TRAF6. Adv Exp Med Biol. 2007; 597:122-30. DOI: 10.1007/978-0-387-70630-6_10. View

18.

Ning S, Campos A, Darnay B, Bentz G, Pagano J . TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol. 2008; 28(20):6536-46. PMC: 2577435. DOI: 10.1128/MCB.00785-08. View

19.

Yoshida R, Takaesu G, Yoshida H, Okamoto F, Yoshioka T, Choi Y . TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. J Biol Chem. 2008; 283(52):36211-20. PMC: 2662295. DOI: 10.1074/jbc.M806576200. View

20.

Konno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K . TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA. PLoS One. 2009; 4(5):e5674. PMC: 2682567. DOI: 10.1371/journal.pone.0005674. View