SIRT5 is a proviral factor that interacts with SARS-CoV-2 Nsp14 protein

SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a p...

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Vydáno v:PLoS pathogens Ročník 18; číslo 9; s. e1010811
Hlavní autoři: Walter, Marius, Chen, Irene P., Vallejo-Gracia, Albert, Kim, Ik-Jung, Bielska, Olga, Lam, Victor L., Hayashi, Jennifer M., Cruz, Andrew, Shah, Samah, Soveg, Frank W., Gross, John D., Krogan, Nevan J., Jerome, Keith R., Schilling, Birgit, Ott, Melanie, Verdin, Eric
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 01.09.2022
Public Library of Science (PLoS)
Témata:
Aging
Antiviral Agents
Antiviral drugs
Biology and life sciences
Cell culture
Coronaviruses
COVID-19
Editing
Exoribonucleases - metabolism
Genomes
Health aspects
Histones
Humans
Hypotheses
Immune response
Infections
Innate immunity
Lysine
Medicine and health sciences
Metabolism
Methyltransferase
Methyltransferases - metabolism
Mitochondria
NAD
Physical Sciences
Plasmids
Protein turnover
Proteins
Proviruses
Replication
Research and Analysis Methods
RNA polymerase
RNA, Viral - metabolism
SARS-CoV-2
Scientific imaging
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Sirtuins - genetics
Therapeutic applications
Transcription factors
Viral diseases
Viral infections
Viral Nonstructural Proteins - metabolism
United States
ISSN:1553-7374, 1553-7366, 1553-7374
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Popis
Shrnutí:SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response, independently of the Mitochondrial Antiviral Signaling Protein MAVS. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.
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Current address: Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, Washington, United States of America
The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan J. Krogan has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics, Interline Therapeutics, Rezo Therapeutics, GEn1E Lifesciences, Inc. and Twist Bioscience Corp. He is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1010811