tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2019 Aug 7. pii: 201907031. doi: 10.1073/pnas.1907031116. [Epub ahead of print]
[h=1]An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity.[/h] Schmidt N[SUP]1[/SUP], Domingues P[SUP]1[/SUP], Golebiowski F[SUP]1[/SUP], Patzina C[SUP]1[/SUP], Tatham MH[SUP]2[/SUP], Hay RT[SUP]2[/SUP], Hale BG[SUP]3[/SUP].
[h=3]Author information[/h] 1 Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland. 2 Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, DD1 5EH Dundee, United Kingdom. 3 Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland; hale.ben@virology.uzh.ch.
[h=3]Abstract[/h] Dynamic small ubiquitin-like modifier (SUMO) linkages to diverse cellular protein groups are critical to orchestrate resolution of stresses such as genome damage, hypoxia, or proteotoxicity. Defense against pathogen insult (often reliant upon host recognition of "non-self" nucleic acids) is also modulated by SUMO, but the underlying mechanisms are incompletely understood. Here, we used quantitative SILAC-based proteomics to survey pan-viral host SUMOylation responses, creating a resource of almost 600 common and unique SUMO remodeling events that are mounted during influenza A and B virus infections, as well as during viral innate immune stimulation. Subsequent mechanistic profiling focused on a common infection-induced loss of the SUMO-modified form of TRIM28/KAP1, a host transcriptional repressor. By integrating knockout and reconstitution models with system-wide transcriptomics, we provide evidence that influenza virus-triggered loss of SUMO-modified TRIM28 leads to derepression of endogenous retroviral (ERV) elements, unmasking this cellular source of "self" double-stranded (ds)RNA. Consequently, loss of SUMO-modified TRIM28 potentiates canonical cytosolic dsRNA-activated IFN-mediated defenses that rely on RIG-I, MAVS, TBK1, and JAK1. Intriguingly, although wild-type influenza A virus robustly triggers this SUMO switch in TRIM28, the induction of IFN-stimulated genes is limited unless expression of the viral dsRNA-binding protein NS1 is abrogated. This may imply a viral strategy to antagonize such a host response by sequestration of induced immunostimulatory ERV dsRNAs. Overall, our data reveal that a key nuclear mechanism that normally prevents aberrant expression of ERV elements (ERVs) has been functionally co-opted via a stress-induced SUMO switch to augment antiviral immunity.
Copyright ? 2019 the Author(s). Published by PNAS.
[h=4]KEYWORDS:[/h] SUMO; dsRNA; endogenous retroviruses; influenza; interferon
PMID: 31391303 DOI: 10.1073/pnas.1907031116
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[h=1]An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity.[/h] Schmidt N[SUP]1[/SUP], Domingues P[SUP]1[/SUP], Golebiowski F[SUP]1[/SUP], Patzina C[SUP]1[/SUP], Tatham MH[SUP]2[/SUP], Hay RT[SUP]2[/SUP], Hale BG[SUP]3[/SUP].
[h=3]Author information[/h] 1 Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland. 2 Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, DD1 5EH Dundee, United Kingdom. 3 Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland; hale.ben@virology.uzh.ch.
[h=3]Abstract[/h] Dynamic small ubiquitin-like modifier (SUMO) linkages to diverse cellular protein groups are critical to orchestrate resolution of stresses such as genome damage, hypoxia, or proteotoxicity. Defense against pathogen insult (often reliant upon host recognition of "non-self" nucleic acids) is also modulated by SUMO, but the underlying mechanisms are incompletely understood. Here, we used quantitative SILAC-based proteomics to survey pan-viral host SUMOylation responses, creating a resource of almost 600 common and unique SUMO remodeling events that are mounted during influenza A and B virus infections, as well as during viral innate immune stimulation. Subsequent mechanistic profiling focused on a common infection-induced loss of the SUMO-modified form of TRIM28/KAP1, a host transcriptional repressor. By integrating knockout and reconstitution models with system-wide transcriptomics, we provide evidence that influenza virus-triggered loss of SUMO-modified TRIM28 leads to derepression of endogenous retroviral (ERV) elements, unmasking this cellular source of "self" double-stranded (ds)RNA. Consequently, loss of SUMO-modified TRIM28 potentiates canonical cytosolic dsRNA-activated IFN-mediated defenses that rely on RIG-I, MAVS, TBK1, and JAK1. Intriguingly, although wild-type influenza A virus robustly triggers this SUMO switch in TRIM28, the induction of IFN-stimulated genes is limited unless expression of the viral dsRNA-binding protein NS1 is abrogated. This may imply a viral strategy to antagonize such a host response by sequestration of induced immunostimulatory ERV dsRNAs. Overall, our data reveal that a key nuclear mechanism that normally prevents aberrant expression of ERV elements (ERVs) has been functionally co-opted via a stress-induced SUMO switch to augment antiviral immunity.
Copyright ? 2019 the Author(s). Published by PNAS.
[h=4]KEYWORDS:[/h] SUMO; dsRNA; endogenous retroviruses; influenza; interferon
PMID: 31391303 DOI: 10.1073/pnas.1907031116
Free full text