1. An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity
- Author
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Filip Golebiowski, Patricia Domingues, Benjamin G. Hale, Corinna Patzina, Ronald T. Hay, Nora Schmidt, Michael H. Tatham, University of Zurich, and Hale, Benjamin G
- Subjects
10028 Institute of Medical Virology ,SUMO-1 Protein ,SUMO protein ,Endogenous retrovirus ,610 Medicine & health ,dsRNA ,Tripartite Motif-Containing Protein 28 ,Biology ,Virus Replication ,medicine.disease_cause ,Models, Biological ,Virus ,03 medical and health sciences ,Immunology and Inflammation ,0302 clinical medicine ,Interferon ,Influenza, Human ,Influenza A virus ,medicine ,Animals ,Humans ,RNA, Double-Stranded ,030304 developmental biology ,1000 Multidisciplinary ,0303 health sciences ,Multidisciplinary ,Innate immune system ,Endogenous Retroviruses ,Sumoylation ,interferon ,Biological Sciences ,Immunity, Innate ,3. Good health ,Cell biology ,RNA silencing ,PNAS Plus ,Proteotoxicity ,SUMO ,Host-Pathogen Interactions ,570 Life sciences ,biology ,Microbial Interactions ,influenza ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Significance Primary host defenses against viruses involve specific cellular recognition of non-self nucleic acids as pathogen-associated molecular patterns (PAMPs) that trigger induction of cytokine-mediated antiviral responses. Thus, ability to discriminate between “self” and “non-self” nucleic acids, and prevent aberrant immunopathology, is a key tenet of immunity. Here, we identify self-derived endogenous retroviral RNAs as host-encoded PAMPs that are up-regulated during influenza virus infections, and which stimulate antiviral immunity. Normally, endogenous retroviruses are tightly repressed transcriptionally by host TRIM28, but infection triggers changes in the modification status of TRIM28 to alleviate repression. This provides an example of how endogenous retroviruses integrated within the host genome have been functionally co-opted by a regulatory switch to aid defense against newly invading pathogens., 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.
- Published
- 2019
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