Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-κB–dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-κB-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-β (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines.
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Gene Expression Omnibus
We thank M. Dasso (US National Institutes of Health) for antibody to SUMO-2; A. Garcia-Sastre(Icahn School of Medicine at Mount Sinai) for antibody to HA; A. Andrieux and J.-M. Carpier for technical help; Philippe Sansonetti (Pasteur Institute, Paris) for S. flexneri; and M. Yaniv for critical reading of the manuscript. Sequencing was performed by the Institut Génétique Biologie Moléculaire Cellulaire Microarray and Sequencing platform, a member of the 'France Génomique' consortium (ANR-10-INBS-0009). Supported by Institut National du Cancer (PLBIO13-057 to S.A.), Agence Nationale de la Recherche (ANR-14-CE16 to S.A.), Ligue Nationale Contre le Cancer (Equipes labellisées, A. Dejean and S.A.), Fondation pour la Recherche Médicale (FRM, AJE201212 to O.J.), Région-Midi-Pyrénées (NVEQ 2014 to O.J.), European Research Council ('SUMOSTRESS' to A. Dejean, 'DC-BIOX340046' to S.A., and 'HIVINNATE' (309848) to N.M.), Ecole Normale Supérieure (A. Decque) and Odyssey-RE (A. Decque).
Integrated supplementary information
List of 224 genes differentially expressed in unstimulated Ubc9+/+ vs Ubc9-/- BMDCs as determined by microarray analysis in 3 biological replicates (fold change 2 or -2, p <0.05, Bonferroni).
List of 880 genes differentially expressed in Ubc9+/+ vs Ubc9-/ BMDCs treated by LPS for 6h as determined by microarray analysis in 3 biological replicates performed in triplicates (fold change 2 or -2, p <0.05, Bonferroni).
List of LPS-induced, -reduced and -unaffected SUMO-2 peaks in BMDCs. In sheet 1, SUMO-2 peaks enriched at 2 h (as compared to the untreated sample) with a p < 10−5 are shown with their main features, including chromosomal location, p value, RefSeq and gene description. Peaks were ordered by p value. Peaks were color-coded as follows: green, intergenic; brown, non-coding; yellow, peaks surrounding TSS of RefSeq genes; dark blue, intronic; grey, exonic; orange, 3'UTR; light blue, 5'UTR; and red, TTS. In sheet 2, SUMO-2 peaks reduced at 2h (as compared to the untreated sample) with a p < 10−5 are shown as in sheet 1. In sheet 3, list of unaffected SUMO-2 peaks detected in untreated sample as in sheet 1.
List of the LPS-stimulated genes associated with induced SUMO-2 peaks. The top 5 GO categories are shown.
List of LPS-induced and non-induced SUMO-1 peaks in BMDCs. In sheet 1, SUMO-1 peaks enriched at 2 h (as compared to the untreated sample) with a p<10−5 are shown with their main features, including chromosomal location, p value, RefSeq and gene description. Peaks were ordered by p value. Peaks were color-coded as follows: green, intergenic; brown, non-coding; yellow, peaks surrounding TSS of RefSeq genes; dark blue, intronic; grey, exonic; orange, 3'UTR; light blue, 5'UTR; and red, TTS. In sheet 2, list of non-inducible SUMO-1 peaks detected in untreated sample as in sheet 1.
List of primers and siRNAs used in this study. siRNAs and primers that were used for RT-qPCR, ChIP-qPCR and plasmid cloning are shown.
About this article
Cellular & Molecular Immunology (2016)