Abstract
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.
Highlights
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
We extended our previous survey of the host SUMOylation response to influenza A virus (IAV) infection [28] by applying quantitative proteomic strategies to identify cellular proteins that change in SUMO modification status following infection with the distantly related influenza B virus (IBV), or an IAV strain engineered to lack expression of its major IFN-antagonist protein, NS1 (IAVΔNS1)
The major experimental focus of this study was to determine the consequences of infection-triggered loss of SUMOylated TRIM28, a cellular reaction to all 3 influenza virus infection states that we found to be independent of canonical innate immune stimulation and DNA damage-like stimuli involving the ATM kinase
Summary
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. TRIM28 is a transcriptional corepressor that acts in concert with KRAB-ZNFs (Krüppel-associated box domain-zinc finger proteins), SUMO, the histone methyltransferase SETDB1, and the nucleosome remodeling and deacetylation (NuRD) complex to induce heterochromatin formation and repress endogenous retroviral (ERV) element transcription [22,23,24,25,26,27] Such silencing of ERV elements (ERVs) is critical to limit aberrant IFN responses, as artificial derepression of ERV transcripts leads to formation of double-stranded RNA (dsRNA) that is sensed as non-self by PRRs [5,6,7,8,9,10]. Our data add insights into how mammals have evolved to take advantage of non-self elements integrated within their genomes, and provide an example of how traditional self versus nonself rules have been usurped in order to counteract virus infection
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