Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses

Zhao, Min; Zhang, Yaolin; Yang, Xinglun; Jin, Jiayang; Shen, Zhuo; Feng, Xiaoyao; Zou, Tong; Deng, Lijiao; Cheng, Dao-Hai; Zhang, Xueting; Qin, Cheng; Niu, Chunxiao; Ye, Zhenjie; Zhang, Xueying; He, Jia; Hou, Chunmei; Li, Ge; Han, Gencheng; Cheng, Qianqian; Wang, Qingyang; Wei, Lin; Dong, Jing; Zhang, Jiyan

doi:10.1371/journal.ppat.1009901

Cited by 20 publications

(19 citation statements)

References 58 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They also claimed that neddylation inhibition increases zebrafish sensitivity to SVCV infection. And tests about SeV infection showed similar results, demonstrating that during infection, NEDD8 directly targets the C-terminal lysine residues of IRF7 ( Figure 3 ) and partially improves its transcription by inhibiting its dimerization with the IFN-α repressor, IRF5 ( Zhao et al, 2021 ). Through neddylation, induction of type I IFN by RNA virus is promoted, especially that of IFN-α.…”

Section: Neddylation and Anti-viral Pathwaysmentioning

confidence: 73%

“…Zhao et al used mouse models with myeloid deficiency in UBA3 or NEDD8 to study the effects of neddylation on the response against RNA virus, and they found UBA3 absence results in impaired IFN-β (interferon-β) as well as IFN-α production in myeloid dendritic cells (mDCs), proposing that myeloid neddylation is required to induce IFN production upon Sendai virus (SeV) infection ( Zhao et al, 2021 ). Previous studies on zebrafish demonstrated that both interferon regulatory factor 3 (IRF3) and IRF7 are potential substrates of neddylation during spring viremia of carp virus (SVCV) infection and can activate anti-viral responses ( Yu et al, 2019 ).…”

Section: Neddylation and Anti-viral Pathwaysmentioning

confidence: 99%

“…Neddylation is a form of post-translational protein modifications (PTMs) in which the ubiquitin-like protein neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8) binds to the target protein via a process similar to ubiquitination ( Yu et al, 2019 ; Zhao et al, 2021 ). It was reported that the sequences of NEDD8 and ubiquitin are 59% identical ( Figure 1A ) ( Enchev et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Association Between Neddylation and Immune Response

Zhu

Zhang

Sun

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Neddylation is a ubiquitin-like post-translational protein modification. It occurs via the activation of the neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8) by three enzymes: activating enzyme, conjugating enzyme, and ligase. NEDD8 was first isolated from the mouse brain in 1992 and was initially considered important for the development and differentiation of the central nervous system. Previously, the downregulation of neddylation was associated with some human diseases, such as neurodegenerative disorders and cancers. In recent years, neddylation has also been proven to be pivotal in various processes of the human immune system, including the regulation of inflammation, bacterial infection, viral infection, and T cell function. Additionally, NEDD8 was found to act on proteins that can affect viral transcription, leading to impaired infectivity. Here, we focused on the influence of neddylation on the innate and adaptive immune responses.

show abstract

Section: Neddylation and Anti-viral Pathwaysmentioning

confidence: 73%

Section: Neddylation and Anti-viral Pathwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Association Between Neddylation and Immune Response

Zhu

Zhang

Sun

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…The PR-UBA3 interaction has notable implications for impacting antiviral immunity, based on strong evidence for a necessity of NEDDylation-associated cullin-RING E3 ubiquitin ligases in retroviral infections, as a means to overcome cellular viral restriction factors APOBEC and SAMHD1 (94). However, given the broad antiviral effect of NEDDylation inhibitor MLN4924 (95), and the role of NEDDylation in activating NF-kB, IRFs, and interferon production (96,97), it remains unclear how PR involvement in NEDDylation may impact ERVK activity.…”

Section: Ervk Protease Is Associated With the Apex Of Ubiquitin-like ...mentioning

confidence: 99%

Predicted cellular interactors of the endogenous retrovirus-K protease enzyme

Narvey¹,

Vandenakker²,

Rempel³

et al. 2022

Front. Virol.

View full text Add to dashboard Cite

Retroviral proteases are essential enzymes for viral replication and drive changes within the cellular proteome. While several studies have demonstrated that protease (PR) enzymes from exogenous retroviruses cleave cellular proteins and modulate cellular signaling, the impact of PRs encoded by endogenous retroviruses within the human genome has been largely overlooked. One human symbiont called Endogenous retrovirus-K (ERVK) is pathologically associated with both neurological disease and cancers. Using a computational biology approach, we sought to characterize the ERVK PR interactome. The ERVK PR protein sequence was analyzed using the Eukaryotic Linear Motif (ELM) database and results compared to ELMs of other betaretroviral PRs and similar endogenated viral PRs. A list of putative ERVK PR cellular protein interactors was curated from the ELM list and submitted for STRING analysis to generate an ERVK PR interactome. Reactome analysis was used to identify key pathways potentially influenced by ERVK PR. Network analysis postulated that ERVK PR interacts at the apex of several ubiquitination pathways, as well as has a role in the DNA damage response, gene regulation, and intracellular trafficking. Among retroviral PRs, a predicted interaction with proliferating cell nuclear antigen (PCNA) was unique to ERVK PR. The most prominent disease-associated pathways identified were viral carcinogenesis and neurodegeneration. This strengthens the role of ERVK PR in these pathologies by putatively driving alterations in cellular signaling cascades via select protein-protein interactions.

show abstract

“…5c). UBE2F is involved in neddylation, a posttranslational modification required for the nuclear translocation of IRF7 by myeloid cells following infection with RNA viruses and, thus, for the induction of type I IFN responses 47 . Collectively, these results document the molecular and cellular mechanisms through which archaic introgression has altered immune functions.…”

Section: Introductionmentioning

confidence: 99%

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Aquino

Bisiaux

et al. 2022

Preprint

View full text Add to dashboard Cite

Humans display vast clinical variability upon SARS-CoV-2 infection, partly due to genetic and immunological factors. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

show abstract

Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses

Cited by 20 publications

References 58 publications

Association Between Neddylation and Immune Response

Association Between Neddylation and Immune Response

Predicted cellular interactors of the endogenous retrovirus-K protease enzyme

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Contact Info

Product

Resources

About