3C protease of enterovirus 71 cleaves promyelocytic leukemia protein and impairs PML-NBs production.

3C Viral Proteases Enterovirus Enterovirus A, Human Peptide Hydrolases Promyelocytic Leukemia Protein / genetics
3C protease Cleavage Enterovirus 71 (EV71) PML nuclear bodies (PML-NBs) Promyelocytic leukemia (PML)

Journal

Virology journal
ISSN: 1743-422X
Titre abrégé: Virol J
Pays: England
ID NLM: 101231645

Informations de publication

Date de publication:
20 12 2021
Historique:
received: 16 09 2021
accepted: 08 12 2021
entrez: 21 12 2021
pubmed: 22 12 2021
medline: 12 3 2022
Statut: epublish

Résumé

Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. Effective drug for preventing and treating EV71 infection is unavailable currently. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. Promyelocytic leukemia (PML) protein, the primary organizer of PML nuclear bodies (PML-NBs), can be induced by interferon and is involved in antiviral activity. PML inhibits EV71 replication, and EV71 infection reduces PML expression, but the molecular mechanism is unclear. The cleavage of PMLIII and IV was confirmed by co-transfection of EV71 3C protease and PML. The detailed cleavage sites were evaluated further by constructing the Q to A mutant of PML. PML knockout cells were infected with EV71 to identify the effect of cleavage on EV71 replication. Immunofluorescence analysis to examine the interference of EV71 3C on the formation of PML-NBs. EV71 3C directly cleaved PMLIII and IV. Furthermore, 3C cleaved PMLIV at the sites of Q430-A431 and Q444-S445 through its protease activity. Overexpression of PMLIV Q430A/Q444A variant exhibited stronger antiviral potential than the wild type. PMLIV Q430A/Q444A formed normal nuclear bodies that were not affected by 3C, suggesting that 3C may impair PML-NBs production via PMLIV cleavage and counter its antiviral activities. PML, especially PMLIV, which sequesters viral proteins in PML-NBs and inhibits viral production, is a novel target of EV71 3C cleavage. EV71 3C cleaves PMLIV at Q430-A431 and Q444-S445. Cleavage reduces the antiviral function of PML and decomposes the formation of PML-NBs, which is conducive to virus replication.

Sections du résumé

BACKGROUND
Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. Effective drug for preventing and treating EV71 infection is unavailable currently. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. Promyelocytic leukemia (PML) protein, the primary organizer of PML nuclear bodies (PML-NBs), can be induced by interferon and is involved in antiviral activity. PML inhibits EV71 replication, and EV71 infection reduces PML expression, but the molecular mechanism is unclear.
METHODS
The cleavage of PMLIII and IV was confirmed by co-transfection of EV71 3C protease and PML. The detailed cleavage sites were evaluated further by constructing the Q to A mutant of PML. PML knockout cells were infected with EV71 to identify the effect of cleavage on EV71 replication. Immunofluorescence analysis to examine the interference of EV71 3C on the formation of PML-NBs.
RESULTS
EV71 3C directly cleaved PMLIII and IV. Furthermore, 3C cleaved PMLIV at the sites of Q430-A431 and Q444-S445 through its protease activity. Overexpression of PMLIV Q430A/Q444A variant exhibited stronger antiviral potential than the wild type. PMLIV Q430A/Q444A formed normal nuclear bodies that were not affected by 3C, suggesting that 3C may impair PML-NBs production via PMLIV cleavage and counter its antiviral activities. PML, especially PMLIV, which sequesters viral proteins in PML-NBs and inhibits viral production, is a novel target of EV71 3C cleavage.
CONCLUSIONS
EV71 3C cleaves PMLIV at Q430-A431 and Q444-S445. Cleavage reduces the antiviral function of PML and decomposes the formation of PML-NBs, which is conducive to virus replication.

Identifiants

DOI: 10.1186/s12985-021-01725-7 PMID: 34930370 PMC: PMC8686290
pubmed: 34930370
doi: 10.1186/s12985-021-01725-7
pii: 10.1186/s12985-021-01725-7
pmc: PMC8686290
doi:

Substances chimiques

Promyelocytic Leukemia Protein 0
Peptide Hydrolases EC 3.4.-
3C Viral Proteases EC 3.4.22.28

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

255

Informations de copyright

© 2021. The Author(s).

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Auteurs

Zhuoran Li (Z)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China.

Ya'ni Wu (Y)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China.

Hui Li (H)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China.

Wenqian Li (W)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China.

Juan Tan (J)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China. juantan@nankai.edu.cn.

Wentao Qiao (W)

Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China. wentaoqiao@nankai.edu.cn.
ORCID: 0000-0003-0449-694X

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales non structurales › Protéases virales › Protéases virales 3C › 3C protease of enterovirus 71 cleaves...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Picornaviridae › Enterovirus › 3C protease of enterovirus 71 cleaves...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Picornaviridae › Enterovirus › Entérovirus humain A › 3C protease of enterovirus 71 cleaves...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › 3C protease of enterovirus 71 cleaves...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines à motif tripartite › Protéine de la leucémie promyélocytaire › 3C protease of enterovirus 71 cleaves...