Global Reprogramming of Host SUMOylation during Influenza Virus Infection

Dynamic nuclear SUMO modifications play essential roles in orchestrating cellular responses to proteotoxic stress, DNA damage, and DNA virus infection. Here, we describe a non-canonical host SUMOylation response to the nuclear-replicating RNA pathogen, influenza virus, and identify viral RNA polymerase activity as a major contributor to SUMO proteome remodeling. Using quantitative proteomics to compare stress-induced SUMOylation responses, we reveal that influenza virus infection triggers unique re-targeting of SUMO to 63 host proteins involved in transcription, mRNA processing, RNA quality control, and DNA damage repair. This is paralleled by widespread host deSUMOylation. Depletion screening identified ten virus-induced SUMO targets as potential antiviral factors, including C18orf25 and the SMC5/6 and PAF1 complexes. Mechanistic studies further uncovered a role for SUMOylation of the PAF1 complex component, parafibromin (CDC73), in potentiating antiviral gene expression. Our global characterization of influenza virus-triggered SUMO redistribution provides a proteomic resource to understand host nuclear SUMOylation responses to infection. [Display omitted] •Nuclear-replicating RNA viruses trigger a host SUMOylation response•Influenza virus RNA polymerase activity contributes to SUMO remodeling•Influenza virus infection re-targets SUMO to a unique set of 63 host proteins•SUMOylation of parafibromin (CDC73) potentiates antiviral gene expression Dynamic SUMOylation is essential for cellular stress responses. Here, Domingues et al. describe a host SUMOylation response to nuclear-replicating influenza viruses. Using quantitative proteomics and functional screening, they reveal that infection uniquely re-targets SUMO to a diverse set of host proteins involved in transcription, RNA processing, and DNA damage repair.