The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation

Li, Zhaolong; Hao, Pengfei; Zhao, Zhilei; Gao, Wenying; Chen, Huan; Li, Letian; Chen, Xiang; Wang, Hong; Jin, Ningyi; Luo, Zhao‐Qing; Li, Chang; Zhang, Wenyan

doi:10.1038/s41392-023-01335-5

Cited by 23 publications

(18 citation statements)

References 41 publications

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“…The genome-wide scan peak at the HLA region contains 148 genes, of which we predict 12 to have significant changes in expression (Figure 2C, Table 2). The most significant signal was for RNF5 , which is involved in the degradation of misfolded proteins and regulation of viral infection (Li et al, 2023; Zeng et al, 2021). Another signal of interest in this region is for decreased expression of C4A , the expression of which is associated with increased risk for schizophrenia (Yilmaz et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Predicting functional consequences of recent natural selection in Britain

Poyraz,

Colbran,

Mathieson

2023

Preprint

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Ancient DNA can directly reveal the contribution of natural selection to human genomic variation. However, while the analysis of ancient DNA has been successful at identifying genomic signals of selection, inferring the phenotypic consequences of that selection has been more difficult. Most trait-associated variants are non-coding, so we expect that a large proportion of the phenotypic effects of selection will also act through non-coding variation. Since we cannot measure gene expression directly in ancient individuals, we used an approach (Joint-Tissue Imputation; JTI) developed to predict gene expression from genotype data. We tested for changes in the predicted expression of 17,384 protein coding genes over a time transect of 4500 years using 91 present-day and 616 ancient individuals from Britain. We identified 28 genes at seven genomic loci with significant (FDR < 0.05) changes in predicted expression levels in this time period. We compared the results from our transcriptome-wide scan to a genome-wide scan based on estimating per-SNP selection coefficients from time series data. At five previously identified loci, our approach allowed us to highlight small numbers of genes with evidence for significant shifts in expression from peaks that in some cases span tens of genes. At two novel loci (SLC44A5 and NUP85), we identify selection on gene expression not captured by scans based on genomic signatures of selection. Finally we show how classical selection statistics (iHS and SDS) can be combined with JTI models to incorporate functional information into scans that use present-day data alone. These results demonstrate the potential of this type of information to explore both the causes and consequences of natural selection.

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Section: Resultsmentioning

confidence: 99%

Predicting functional consequences of recent natural selection in Britain

Poyraz,

Colbran,

Mathieson

2023

Preprint

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“…The polyubiquitinated viral proteins then recruit the IKK kinase complex and NEMO to activate the antiviral response signaled by NF-κB. Another E3 RNF5 has been found to catalyze the ubiquitination of the E protein of SARS-CoV-2 that would lead to the degradation of E by the UPS and inhibition of virus replication . MARCH8 E3 ubiquitinates the viral spike protein and induces its degradation to manifest its antiviral function .…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication

Zhou,

Liu,

Pathak

et al. 2024

ACS Infect. Dis.

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The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (M pro , also known as 3CLpro or Nsp5) to proteolytically process the polyproteins encoded by the viral genome for the release of functional units in the host cells to initiate viral replication. M pro also interacts with host proteins of the innate immune pathways, such as IRF3 and STAT1, to suppress their activities and facilitate virus survival and proliferation. To identify the host mechanism for regulating M pro , we screened various classes of E3 ubiquitin ligases and found that Parkin of the RING-between-RING family can induce the ubiquitination and degradation of M pro in the cell. Furthermore, when the cells undergo mitophagy, the PINK1 kinase activates Parkin and enhances the ubiquitination of M pro . We also found that elevated expression of Parkin in the cells significantly decreased the replication of SARS-CoV-2 virus. Interestingly, SARS-CoV-2 infection downregulates Parkin expression in the mouse lung tissues compared to healthy controls. These results suggest an antiviral role of Parkin as a ubiquitin ligase targeting M pro and the potential for exploiting the virus−host interaction mediated by Parkin to treat SARS-CoV-2 infection.

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“…5,6,31 The UPS acts as an antiviral mechanism by selectively targeting the viral proteins, such as envelope protein of severe acute respiratory syndrome coronavirus 2, 2BC protein of human enteroviruses, and M2 protein of influenza A virus. [32][33][34] The virus in turn has evolved to manipulate UPS to favor its life cycle. For instance, ubiquitination of the viral envelope protein by the E3 ubiquitin ligase TRIM7 facilitated Zika virus entry into host cells.…”

Section: Discussionmentioning

confidence: 99%

“…Host UPS has vital roles in viral propagation and pathogenesis 5,6,31 . The UPS acts as an antiviral mechanism by selectively targeting the viral proteins, such as envelope protein of severe acute respiratory syndrome coronavirus 2, 2BC protein of human enteroviruses, and M2 protein of influenza A virus 32–34 . The virus in turn has evolved to manipulate UPS to favor its life cycle.…”

Section: Discussionmentioning

confidence: 99%

SPOP inhibits HBV transcription and replication by ubiquitination and degradation of HNF1α

Pi,

Li,

Yan

et al. 2023

Journal of Medical Virology

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Hepatitis B virus (HBV) infection remains a significant public health burden worldwide. The persistence of covalently closed circular DNA (cccDNA) within the nucleus of infected hepatocytes is responsible for the failure of antiviral treatments. The ubiquitin proteasome system (UPS) has emerged as a promising antiviral target, as it can regulate HBV replication by promoting critical protein degradation in steps of viral life cycle. Speckle‐type POZ protein (SPOP) is a critical adaptor for Cul3‐RBX1 E3 ubiquitin ligase complex, but the effect of SPOP on HBV replication is less known. Here, we identified SPOP as a novel host antiviral factor against HBV infection. SPOP overexpression significantly inhibited the transcriptional activity of HBV cccDNA without affecting cccDNA level in HBV‐infected HepG2‐NTCP and primary human hepatocyte cells. Mechanism studies showed that SPOP interacted with hepatocyte nuclear factor 1α (HNF1α), and induced HNF1α degradation through host UPS pathway. Moreover, the antiviral role of SPOP was also confirmed in vivo. Together, our findings reveal that SPOP is a novel host factor which inhibits HBV transcription and replication by ubiquitination and degradation of HNF1α, providing a potential therapeutic strategy for the treatment of HBV infection.

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The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation

Cited by 23 publications

References 41 publications

Predicting functional consequences of recent natural selection in Britain

Predicting functional consequences of recent natural selection in Britain

Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication

SPOP inhibits HBV transcription and replication by ubiquitination and degradation of HNF1α

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