SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7 DOI Open Access
Tian Li, Zongzheng Zhao, Wenying Gao

et al.

Published: Dec. 24, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for disease 2019 (COVID-19), remains a global public health threat with major economic implications. The non-structural protein 16 (nsp16) of SARS-CoV-2, in complex nsp10, catalyses final step viral mRNA capping via its 2’-O-methylase activity, enabling to evade host immunity and protect from degradation. However, factors regulating nsp16 have not been thoroughly explored. Although various E3 ubiquitin ligases are known interact SARS-CoV-2 proteins, their specific roles targeting degradation remain unclear. In this study, we demonstrate that is ubiquitinated degraded by UBR5 MARCHF7, acting through ubiquitin-proteasome system (UPS). MARCHF7 induce K48- K27-linked ubiquitination, respectively, independent processes inhibit replication both vitro vivo. Furthermore, exhibited broad-spectrum antiviral activity degrading variants different strains. Our findings uncover novel mechanisms which UPS antagonises provide promising targets therapeutic intervention against COVID-19.

Language: Английский

Protein neddylation and its role in health and diseases DOI Creative Commons
Shizhen Zhang, Qing Yu, Zhijian Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 4, 2024

Abstract NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like that covalently attached to a lysine residue of substrate through process known as neddylation, catalyzed by the enzyme cascade, namely activating (E1), conjugating (E2), and ligase (E3). The substrates neddylation are categorized into cullins non-cullin proteins. Neddylation activates CRLs (cullin RING ligases), largest family E3 ligases, whereas alters their stability activity, well subcellular localization. Significantly, pathway and/or many abnormally activated or over-expressed in various human diseases, such metabolic disorders, liver dysfunction, neurodegenerative cancers, among others. Thus, targeting becomes attractive strategy for treatment these diseases. In this review, we first provide general introduction on its biochemical regulation, crystal structures enzymes complex with cullin substrates; then discuss how governs key biological processes via modification substrates. We further review literature data dysregulated several particularly cancer, followed outline current efforts discovery small molecule inhibitors promising therapeutic approach. Finally, few perspectives were proposed extensive future investigations.

Language: Английский

Citations

39
SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5, and MARCHF7 DOI Open Access
Tian Li, Zongzheng Zhao, Wenying Gao

et al.

Published: March 24, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for disease 2019 (COVID-19), remains a global public health threat with major economic implications. The non-structural protein 16 (nsp16) of SARS-CoV-2, in complex nsp10, catalyses final step viral mRNA capping via its 2’-O-methylase activity, enabling to evade host immunity and protect from degradation. However, factors regulating nsp16 have not been thoroughly explored. Although various E3 ubiquitin ligases are known interact SARS-CoV-2 proteins, their specific roles targeting degradation remain unclear. In this study, we demonstrate that is ubiquitinated degraded by UBR5 MARCHF7, acting through ubiquitin-proteasome system (UPS). MARCHF7 induce K48- K27-linked ubiquitination, respectively, independent processes inhibit replication both vitro vivo. Furthermore, exhibited broad-spectrum antiviral activity degrading variants different strains. Our findings uncover novel mechanisms which UPS antagonises provide promising targets therapeutic intervention against COVID-19.

Language: Английский

Citations

0
ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation DOI Creative Commons
Tian Li,

Zhizhong Mi,

Weijing Yang

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease, particularly affecting pediatric populations worldwide. The role ZYG11B, CUL2-complex-associated E3 ubiquitin ligase from the Zyg-11 family, in antiviral defense against EV71 remains unclear. To our knowledge, this study first to reveal that ZYG11B targets VP1 for proteasomal degradation via ubiquitin-proteasome pathway, with CRL2ZYG11B complex activity specifically driving K33-linked ubiquitination. Mass spectrometry immunoprecipitation analyses confirmed interaction between identified key domains required binding both CUL2. Comparative showed ubiquitination sites are highly conserved across related enteroviruses, including CA6, CA16, EVD68. Functional assays further demonstrated restricts these viruses, highlighting its potential as broad-spectrum target. These findings establish critical effector host responses support therapeutic managing enterovirus infections. ligases deubiquitinases have become important topics competition viruses hosts. Here, we an capable degrading structural protein making factor. We proposed inhibitory effect on connecting substrates CUL2, providing new design drugs.

Language: Английский

Citations

0
SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7 DOI Open Access
Tian Li, Zongzheng Zhao, Wenying Gao

et al.

Published: April 24, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of disease 2019 (COVID-19), remains a global public health threat with considerable economic consequences. The non-structural protein 16 (nsp16), in complex nsp10, facilitates final viral mRNA capping step through its 2′-O-methylase activity, helping virus to evade host immunity and prevent degradation. However, nsp16 regulation by factors poorly understood. While various E3 ubiquitin ligases interact SARS-CoV-2 proteins, their roles targeting for degradation are unclear. In this study, we demonstrate that undergoes ubiquitination proteasomal mediated UBR5 MARCHF7. induces K48-linked ubiquitination, whereas MARCHF7 promotes K27-linked independently suppressing replication vitro vivo. Notably, also degrade variants from different strains, exhibiting broad-spectrum antiviral activity. Our findings reveal novel mechanisms ubiquitin-proteasome system (UPS) highlight potential therapeutic targets against COVID-19.

Language: Английский

Citations

0
SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7 DOI Creative Commons

Li Tian,

Zongzheng Zhao, Wenying Gao

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: May 13, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of disease 2019 (COVID-19), remains a global public health threat with considerable economic consequences. The nonstructural protein 16 (nsp16), in complex nsp10, facilitates final viral mRNA capping step through its 2′- O -methylase activity, helping virus to evade host immunity and prevent degradation. However, nsp16 regulation by factors poorly understood. While various E3 ubiquitin ligases interact SARS-CoV-2 proteins, their roles targeting for degradation remain unclear. In this study, we demonstrate that undergoes ubiquitination proteasomal mediated UBR5 MARCHF7. induces K48-linked ubiquitination, whereas MARCHF7 promotes K27-linked independently suppressing replication cell cultures mice. Notably, also degrade variants from different strains, exhibiting broad-spectrum antiviral activity. Our findings reveal novel mechanisms ubiquitin-proteasome system (UPS) highlight potential therapeutic targets against COVID-19.

Language: Английский

Citations

0
HERC5-mediated ISGylation of SARS-CoV-2 nsp8 facilitates its degradation and inhibits viral replication DOI

Yubao Hou,

Hongyun Shi, Huihan Wang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 144546 - 144546

Published: May 1, 2025

Language: Английский

Citations

0
SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7 DOI Creative Commons
Tian Li, Zongzheng Zhao, Wenying Gao

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for disease 2019 (COVID-19), remains a global public health threat with major economic implications. The non-structural protein 16 (nsp16) of SARS-CoV-2, in complex nsp10, catalyses final step viral mRNA capping via its 2’-O-methylase activity, enabling to evade host immunity and protect from degradation. However, factors regulating nsp16 have not been thoroughly explored. Although various E3 ubiquitin ligases are known interact SARS-CoV-2 proteins, their specific roles targeting degradation remain unclear. In this study, we demonstrate that is ubiquitinated degraded by UBR5 MARCHF7, acting through ubiquitin-proteasome system (UPS). MARCHF7 induce K48- K27-linked ubiquitination, respectively, independent processes inhibit replication both vitro vivo. Furthermore, exhibited broad-spectrum antiviral activity degrading variants different strains. Our findings uncover novel mechanisms which UPS antagonises provide promising targets therapeutic intervention against COVID-19.

Language: Английский

Citations

0
Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection DOI Creative Commons

Jesse Pellman,

Anna Goldstein,

Mikołaj Słabicki

et al.

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 2, 2024

E3 ubiquitin ligases regulate the composition of proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function targeting proteins for degradation by proteasome. In this review, we discuss opposing roles human as effectors and targets in evolutionary battle between host pathogen, specifically context SARS-CoV-2 infection. Through complex effects on transcription, translation, trafficking, can either attenuate infection become vulnerabilities that are exploited virus to suppress host's antiviral defenses. For example, ligase RNF185 regulates stability envelope through ubiquitin-proteasome pathway, depletion significantly increases viral titer (iScience (2023) 26, 106601). We highlight recent advances identify functions numerous life cycle assess potential novel agents.

Language: Английский

Citations

0
E3 ubiquitin ligase FBXO22 inhibits SARS‐CoV‐2 replication via promoting proteasome‐dependent degradation of NSP5 DOI
Yuzheng Zhou, Wei Feng, Chuwei Yang

et al.

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(9)

Published: Sept. 1, 2024

The ubiquitin-proteasome system is frequently employed to degrade viral proteins, thereby inhibiting replication and pathogenicity. Through an analysis of the degradation kinetics all SARS-CoV-2 our study revealed rapid several particularly NSP5. Additionally, we identified FBXO22, E3 ubiquitin ligase, as primary regulator NSP5 ubiquitination. Moreover, validated interaction between FBXO22 NSP5, demonstrating that FBXO22-mediated ubiquitination facilitated its recognition by proteasome, leading subsequent degradation. Specifically, catalyzed formation K48-linked polyubiquitin chains on at lysine residues 5 90. Knockdown resulted in decreased levels, increased stability, enhanced ability evade host innate immune response. Notably, protein level were negatively correlated with load, highlighting importance replication. This elucidates molecular mechanism which mediates underscores critical role limiting identification a stability provides new insights potential avenues for targeting antiviral strategies.

Language: Английский

Citations

0
Pellino-1, a therapeutic target for control of SARS-CoV-2 infection and disease severity DOI
Binbin Wang, Hongjie Xia, Bi‐Hung Peng

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: unknown, P. 106059 - 106059

Published: Dec. 1, 2024

Language: Английский

Citations

0