Neddylation Facilitates the Antiviral Response in Zebrafish

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2019 Jul 12

PMID 31293590

Citations 13

Authors

Guangqing Yu

Xing Liu

Jinhua Tang

Chenxi Xu

Gang Ouyang

Wuhan Xiao

Affiliations

Soon will be listed here.

Abstract

Neddylation is a type of post-translational protein modifications, in which neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) is covalently conjugated to the lysine residues of target substrates. The best characterized principal substrates of neddylation are the cullin-RING ligases (CRLs). In addition, neddylation also modifies non-cullin proteins to affect gene regulation, cell survival, organ development, and stress response. However, the role of neddylation in antiviral innate immunity remain largely unknown. Here, we found that when neddylation was blocked by the NEDD8 activating enzyme E1 (NAE) inhibitor, MLN4924, the cellular and organismal antiviral response was suppressed. Moreover, the disruption of increased the sensitivity of zebrafish to SVCV infection. Further assays indicated that blocking or silencing neddylation significantly downregulated key antiviral genes after poly (I:C) stimulation or SVCV infection, but dramatically increased SVCV replication. Neddylation of Irf3 and Irf7 was readily detected, but not of Mda5, Mavs, and Tbk1. Thus, our results not only demonstrated that neddylation facilitated the antiviral response and , but also revealed a novel role of in antiviral innate immunity.

Citing Articles

Zebrafish enhances mavs-mediated antiviral responses in a hydroxylation-independent manner.

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Unconventional posttranslational modification in innate immunity.

Chen J, Qi D, Hu H, Wang X, Lin W Cell Mol Life Sci. 2024; 81(1):290.

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Protein neddylation and its role in health and diseases.

Zhang S, Yu Q, Li Z, Zhao Y, Sun Y Signal Transduct Target Ther. 2024; 9(1):85.

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Neddylation Regulation of Immune Responses.

Mao H, Lin X, Sun Y Research (Wash D C). 2024; 6:0283.

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IRF7: role and regulation in immunity and autoimmunity.

Ma W, Huang G, Wang Z, Wang L, Gao Q Front Immunol. 2023; 14:1236923.

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References

Gan-Erdene T, Nagamalleswari K, Yin L, Wu K, Pan Z, Wilkinson K . Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem. 2003; 278(31):28892-900. DOI: 10.1074/jbc.M302890200. View

Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A . DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1. J Biol Chem. 2003; 278(31):28882-91. DOI: 10.1074/jbc.M302888200. View

Xirodimas D, Saville M, Bourdon J, Hay R, Lane D . Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell. 2004; 118(1):83-97. DOI: 10.1016/j.cell.2004.06.016. View

Watson I, Blanch A, Lin D, Ohh M, Irwin M . Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. J Biol Chem. 2006; 281(45):34096-103. DOI: 10.1074/jbc.M603654200. View

Gao F, Cheng J, Shi T, Yeh E . Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription. Nat Cell Biol. 2006; 8(10):1171-7. DOI: 10.1038/ncb1483. View

Rabut G, Peter M . Function and regulation of protein neddylation. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep. 2008; 9(10):969-76. PMC: 2572130. DOI: 10.1038/embor.2008.183. View

Merlet J, Burger J, Gomes J, Pintard L . Regulation of cullin-RING E3 ubiquitin-ligases by neddylation and dimerization. Cell Mol Life Sci. 2009; 66(11-12):1924-38. PMC: 11115538. DOI: 10.1007/s00018-009-8712-7. View

Soucy T, Smith P, Milhollen M, Berger A, Gavin J, Adhikari S . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458(7239):732-6. DOI: 10.1038/nature07884. View

Brownell J, Sintchak M, Gavin J, Liao H, Bruzzese F, Bump N . Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell. 2010; 37(1):102-11. DOI: 10.1016/j.molcel.2009.12.024. View

10.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View

11.

Ryu J, Li S, Park H, Park J, Lee B, Chun Y . Hypoxia-inducible factor α subunit stabilization by NEDD8 conjugation is reactive oxygen species-dependent. J Biol Chem. 2011; 286(9):6963-70. PMC: 3044952. DOI: 10.1074/jbc.M110.188706. View

12.

Watson I, Irwin M, Ohh M . NEDD8 pathways in cancer, Sine Quibus Non. Cancer Cell. 2011; 19(2):168-76. DOI: 10.1016/j.ccr.2011.01.002. View

13.

Loo Y, Gale Jr M . Immune signaling by RIG-I-like receptors. Immunity. 2011; 34(5):680-92. PMC: 3177755. DOI: 10.1016/j.immuni.2011.05.003. View

14.

Chang F, Reyna S, Granados J, Wei S, Innis-Whitehouse W, Maffi S . Inhibition of neddylation represses lipopolysaccharide-induced proinflammatory cytokine production in macrophage cells. J Biol Chem. 2012; 287(42):35756-35767. PMC: 3471689. DOI: 10.1074/jbc.M112.397703. View

15.

Galindo-Villegas J, Garcia-Moreno D, de Oliveira S, Meseguer J, Mulero V . Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during zebrafish development. Proc Natl Acad Sci U S A. 2012; 109(39):E2605-14. PMC: 3465450. DOI: 10.1073/pnas.1209920109. View

16.

Jin H, Liao L, Park Y, Liu Y . Neddylation pathway regulates T-cell function by targeting an adaptor protein Shc and a protein kinase Erk signaling. Proc Natl Acad Sci U S A. 2012; 110(2):624-9. PMC: 3545825. DOI: 10.1073/pnas.1213819110. View

17.

Zuo W, Huang F, Chiang Y, Li M, Du J, Ding Y . c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor. Mol Cell. 2013; 49(3):499-510. DOI: 10.1016/j.molcel.2012.12.002. View

18.

Goubau D, Deddouche S, Reis e Sousa C . Cytosolic sensing of viruses. Immunity. 2013; 38(5):855-69. PMC: 7111113. DOI: 10.1016/j.immuni.2013.05.007. View

19.

Paludan S, Bowie A . Immune sensing of DNA. Immunity. 2013; 38(5):870-80. PMC: 3683625. DOI: 10.1016/j.immuni.2013.05.004. View

20.

Mathewson N, Toubai T, Kapeles S, Sun Y, Oravecz-Wilson K, Tamaki H . Neddylation plays an important role in the regulation of murine and human dendritic cell function. Blood. 2013; 122(12):2062-73. PMC: 3778550. DOI: 10.1182/blood-2013-02-486373. View