Neddylation Facilitates the Antiviral Response in Zebrafish

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 nedd8 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 in vitro and in vivo , but also revealed a novel role of nedd8 in antiviral innate immunity.

Red elemental selenium (Se0) improves the immunoactivities of EPC cells, crucian carp and zebrafish against spring viraemia of carp virus

“…Total RNA was isolated from EPC cells and fish tissues, including kidney, spleen and liver. Quantitative real‐time PCR (qPCR) was performed based on those methods reported previously (Jiang et al ., 2019; Yan et al ., 2017; Yu et al ., 2019). The primers for qPCR are listed in Supporting Information Table S1.…”

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

“…NEDDylation is a process where target proteins undergo covalent attachment to ubiquitin-like molecule NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) [ 77 ]. NEDDylated substrates have been implicated in cancer, DNA damage responses, transcriptional regulation, nucleolar stress signaling, apoptosis, and ubiquitin-proteasome machinery [ 9 ].…”

“…In contrast, the mutant (K699R) showed heightened virulence during infection in mice, highlighting the importance of NEDDylation on viral proteins and replication [ 5 ]. IRF3 and IRF7 were also identified as targets for NEDD8 conjugation [ 77 ], suggesting a direct link between the neddylation of viral proteins and viral replication inhibition. Moreover, the study established that NEDD8 deficient zebrafish larvae and adults were more susceptible to SVCV (Spring viremia of carp virus) infection than wild type [ 77 ].…”

The pivotal roles of neddylation pathway in immunoregulation

“…It is reported that blocking or silencing neddylation dramatically increased spring viremia of carp virus (an ssRNA virus that causes an important disease affecting cyprinids) replication. 87 Zhang et al 88 reported that neddylation of the polymerase basic protein 2 of influenza A virus reduces its stability and blocks the replication of influenza A virus. On the other hand, neddylation inhibition restores the restriction of human immunodeficiency virus by repressing the degradation of host restriction factors, a kind of cellular proteins inhibiting the replication of viruses at various stages of their life cycle.…”

“…First, neddylation is considered to control the amplification and replication of viruses. It is reported that blocking or silencing neddylation dramatically increased spring viremia of carp virus (an ssRNA virus that causes an important disease affecting cyprinids) replication 87 . Zhang et al 88 reported that neddylation of the polymerase basic protein 2 of influenza A virus reduces its stability and blocks the replication of influenza A virus.…”