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TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing

TRIM7 catalyzes the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7′s extreme substrate promiscuity is due to a highly unusual binding m...

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Autores principales: Luptak, Jakub, Mallery, Donna L., Jahun, Aminu S., Albecka, Anna, Clift, Dean, Ather, Osaid, Slodkowicz, Greg, Goodfellow, Ian, James, Leo C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9394474/
https://www.ncbi.nlm.nih.gov/pubmed/35893676
http://dx.doi.org/10.3390/v14081610
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author Luptak, Jakub
Mallery, Donna L.
Jahun, Aminu S.
Albecka, Anna
Clift, Dean
Ather, Osaid
Slodkowicz, Greg
Goodfellow, Ian
James, Leo C.
author_facet Luptak, Jakub
Mallery, Donna L.
Jahun, Aminu S.
Albecka, Anna
Clift, Dean
Ather, Osaid
Slodkowicz, Greg
Goodfellow, Ian
James, Leo C.
author_sort Luptak, Jakub
collection PubMed
description TRIM7 catalyzes the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7′s extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The ‘helix-ΦQ’ degron motif recognized by TRIM7 is reminiscent of the N-end degron system and is found in ~1% of cellular proteins. These features, together with TRIM7′s restricted tissue expression and lack of immune regulation, suggest that viral restriction may not be its physiological function.
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spelling pubmed-93944742022-08-23 TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing Luptak, Jakub Mallery, Donna L. Jahun, Aminu S. Albecka, Anna Clift, Dean Ather, Osaid Slodkowicz, Greg Goodfellow, Ian James, Leo C. Viruses Article TRIM7 catalyzes the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7′s extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The ‘helix-ΦQ’ degron motif recognized by TRIM7 is reminiscent of the N-end degron system and is found in ~1% of cellular proteins. These features, together with TRIM7′s restricted tissue expression and lack of immune regulation, suggest that viral restriction may not be its physiological function. MDPI 2022-07-23 /pmc/articles/PMC9394474/ /pubmed/35893676 http://dx.doi.org/10.3390/v14081610 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Luptak, Jakub
Mallery, Donna L.
Jahun, Aminu S.
Albecka, Anna
Clift, Dean
Ather, Osaid
Slodkowicz, Greg
Goodfellow, Ian
James, Leo C.
TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title_full TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title_fullStr TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title_full_unstemmed TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title_short TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing
title_sort trim7 restricts coxsackievirus and norovirus infection by detecting the c-terminal glutamine generated by 3c protease processing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9394474/
https://www.ncbi.nlm.nih.gov/pubmed/35893676
http://dx.doi.org/10.3390/v14081610
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