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

In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases DOI Creative Commons
Marta Campos Alonso, Klaus‐Peter Knobeloch

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 22, 2024

Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given potential as novel therapeutic targets, it is essential fully understand mechanisms action. Traditionally, observed effects resulting from deficiencies deubiquitinases (DUBs) UBL proteases have often attributed misregulation substrate modification by UBLs. Therefore, much research focused on understanding catalytic activities these proteins. However, this view overlooked possibility DUBs might also significant non-catalytic functions, which more prevalent than previously believed urgently require further investigation. Moreover, multiple examples shown either selective loss only protease activity complete absence can different functional physiological consequences. Furthermore, contain domains binding motifs not modulate but mediate entirely functions. This review aims shed light non-catalytic, moonlighting functions proteases, extend beyond hydrolysis chains just beginning emerge.

Language: Английский

Citations

5
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
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
Identification of common genes and pathways between type 2 diabetes and COVID-19 DOI Creative Commons
Ya Wang, Kai Li,

Shuangyang Mo

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: April 18, 2024

Numerous studies have reported a high incidence and risk of severe illness due to coronavirus disease 2019 (COVID-19) in patients with type 2 diabetes (T2DM). COVID-19 may experience elevated or decreased blood sugar levels even develop diabetes. However, the molecular mechanisms linking these two diseases remain unclear. This study aimed identify common genes pathways between T2DM COVID-19.

Language: Английский

Citations

3
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
Silent risk: the vertical transmission of Oropouche virus DOI

Курмангалиева С.С.,

Priyanka Khopkar-Kale, Srikanth Tripathy

et al.

European Journal of Clinical Microbiology & Infectious Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Language: Английский

Citations

2
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
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
Lung‐Targeted Lipid Nanoparticle‐Delivered siUSP33 Attenuates SARS‐CoV‐2 Replication and Virulence by Promoting Envelope Degradation DOI Creative Commons
Yuzheng Zhou,

Yujie Liao,

Lujie Fan

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 20, 2024

Abstract As a structural protein of SARS‐CoV‐2, the envelope (E) not only plays key role in formation viral particles, but also forms ion channels and has pathogenic functions, including triggering cell death inflammatory responses. The stability E proteins is controlled by host ubiquitin‐proteasome system. By screening human deubiquitinases, it found that ubiquitin‐specific protease 33 (USP33) can enhance depending on its deubiquitinase activity, thereby promoting replication. In absence USP33, are rapidly degraded, leading to reduced load inflammation. Using lipid nanoparticle (LNP) encapsulation siUSP33 adjusting components (ionizable cationic lipids), successfully delivered mouse lung tissues, reducing USP33 expression lungs maintaining knockdown for at least 14 days, effectively suppressing replication virulence. This method delivery allows efficient targeting response acute infections without long‐term deficiency. research, based deubiquitination mechanism protein, demonstrates LNP‐mediated siRNA antiviral anti‐inflammatory responses, offering novel strategy prevention treatment SARS‐CoV‐2.

Language: Английский

Citations

0
SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7 DOI Open Access
Tian Li, Zirui Liu, 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), is a global public health threat with significant economic burden. 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. This function helps evade host immunity and protect from degradation. Current literature has not thoroughly investigated factors that regulate nsp16. Although various E3 ubiquitin ligases are known to interact SARS-CoV-2 proteins, their specific roles targeting nsp16 degradation have been elucidated. Here, we demonstrate ubiquitinated degraded by UBR5 MARCHF7, acting through ubiquitin-proteasome system (UPS). MARCHF7 induce K48-and K27-linked ubiquitination, respectively. Moreover, this either or independent, both processes inhibit replication vitro as well vivo. Further, exhibited broad-spectrum antiviral potential degrading variants different strains. Our findings provide novel insights into role UPS antagonising open new avenues therapeutic interventions against COVID-19.

Language: Английский

Citations

0