Implication of PMLIV in both intrinsic and innate immunity.
PML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-02-01
|
Series: | PLoS Pathogens |
Online Access: | http://europepmc.org/articles/PMC3937294?pdf=render |
id |
doaj-600c387877294db38ec7077776113584 |
---|---|
record_format |
Article |
spelling |
doaj-600c387877294db38ec70777761135842020-11-25T01:58:34ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-02-01102e100397510.1371/journal.ppat.1003975Implication of PMLIV in both intrinsic and innate immunity.Faten El AsmiMohamed Ali MarouiJacques DutrieuxDanielle BlondelSébastien NisoleMounira K Chelbi-AlixPML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. The knockout of PML renders mice more sensitive to vesicular stomatitis virus (VSV). Here we report that among PML isoforms (PMLI to PMLVIIb), only PMLIII and PMLIV confer resistance to VSV. Unlike PMLIII, whose anti-VSV activity is IFN-independent, PMLIV can act at two stages: it confers viral resistance directly in an IFN-independent manner and also specifically enhances IFN-β production via a higher activation of IRF3, thus protecting yet uninfected cells from oncoming infection. PMLIV SUMOylation is required for both activities. This demonstrates for the first time that PMLIV is implicated in innate immune response through enhanced IFN-β synthesis. Depletion of IRF3 further demonstrates the dual activity of PMLIV, since it abrogated PMLIV-induced IFN synthesis but not PMLIV-induced inhibition of viral proteins. Mechanistically, PMLIV enhances IFN-β synthesis by regulating the cellular distribution of Pin1 (peptidyl-prolyl cis/trans isomerase), inducing its recruitment to PML NBs where both proteins colocalize. The interaction of SUMOylated PMLIV with endogenous Pin1 and its recruitment within PML NBs prevents the degradation of activated IRF3, and thus potentiates IRF3-dependent production of IFN-β. Whereas the intrinsic antiviral activity of PMLIV is specific to VSV, its effect on IFN-β synthesis is much broader, since it affects a key actor of innate immune pathways. Our results show that, in addition to its intrinsic anti-VSV activity, PMLIV positively regulates IFN-β synthesis in response to different inducers, thus adding PML/TRIM19 to the growing list of TRIM proteins implicated in both intrinsic and innate immunity.http://europepmc.org/articles/PMC3937294?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Faten El Asmi Mohamed Ali Maroui Jacques Dutrieux Danielle Blondel Sébastien Nisole Mounira K Chelbi-Alix |
spellingShingle |
Faten El Asmi Mohamed Ali Maroui Jacques Dutrieux Danielle Blondel Sébastien Nisole Mounira K Chelbi-Alix Implication of PMLIV in both intrinsic and innate immunity. PLoS Pathogens |
author_facet |
Faten El Asmi Mohamed Ali Maroui Jacques Dutrieux Danielle Blondel Sébastien Nisole Mounira K Chelbi-Alix |
author_sort |
Faten El Asmi |
title |
Implication of PMLIV in both intrinsic and innate immunity. |
title_short |
Implication of PMLIV in both intrinsic and innate immunity. |
title_full |
Implication of PMLIV in both intrinsic and innate immunity. |
title_fullStr |
Implication of PMLIV in both intrinsic and innate immunity. |
title_full_unstemmed |
Implication of PMLIV in both intrinsic and innate immunity. |
title_sort |
implication of pmliv in both intrinsic and innate immunity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2014-02-01 |
description |
PML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. The knockout of PML renders mice more sensitive to vesicular stomatitis virus (VSV). Here we report that among PML isoforms (PMLI to PMLVIIb), only PMLIII and PMLIV confer resistance to VSV. Unlike PMLIII, whose anti-VSV activity is IFN-independent, PMLIV can act at two stages: it confers viral resistance directly in an IFN-independent manner and also specifically enhances IFN-β production via a higher activation of IRF3, thus protecting yet uninfected cells from oncoming infection. PMLIV SUMOylation is required for both activities. This demonstrates for the first time that PMLIV is implicated in innate immune response through enhanced IFN-β synthesis. Depletion of IRF3 further demonstrates the dual activity of PMLIV, since it abrogated PMLIV-induced IFN synthesis but not PMLIV-induced inhibition of viral proteins. Mechanistically, PMLIV enhances IFN-β synthesis by regulating the cellular distribution of Pin1 (peptidyl-prolyl cis/trans isomerase), inducing its recruitment to PML NBs where both proteins colocalize. The interaction of SUMOylated PMLIV with endogenous Pin1 and its recruitment within PML NBs prevents the degradation of activated IRF3, and thus potentiates IRF3-dependent production of IFN-β. Whereas the intrinsic antiviral activity of PMLIV is specific to VSV, its effect on IFN-β synthesis is much broader, since it affects a key actor of innate immune pathways. Our results show that, in addition to its intrinsic anti-VSV activity, PMLIV positively regulates IFN-β synthesis in response to different inducers, thus adding PML/TRIM19 to the growing list of TRIM proteins implicated in both intrinsic and innate immunity. |
url |
http://europepmc.org/articles/PMC3937294?pdf=render |
work_keys_str_mv |
AT fatenelasmi implicationofpmlivinbothintrinsicandinnateimmunity AT mohamedalimaroui implicationofpmlivinbothintrinsicandinnateimmunity AT jacquesdutrieux implicationofpmlivinbothintrinsicandinnateimmunity AT danielleblondel implicationofpmlivinbothintrinsicandinnateimmunity AT sebastiennisole implicationofpmlivinbothintrinsicandinnateimmunity AT mounirakchelbialix implicationofpmlivinbothintrinsicandinnateimmunity |
_version_ |
1724968835796172800 |