Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 35, Pages 17399-17408Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1907031116
Keywords
influenza; SUMO; endogenous retroviruses; dsRNA; interferon
Categories
Funding
- Functional Genomics Center Zurich
- Cytometry Facility, University of Zurich
- European Research Council (ERC) under EU FP7 ERC [335809]
- Swiss National Science Foundation [31003A_182464]
- Cancer Research UK [C434/A13067]
- Wellcome Trust Senior Investigator award [098391/Z/12/Z]
- Stiftung fur Forschung an der Medizinischen Fakultat of the University of Zurich
- European Research Council (ERC) [335809] Funding Source: European Research Council (ERC)
- Wellcome Trust [098391/Z/12/Z] Funding Source: Wellcome Trust
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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.
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