Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing

• Published in: Nature immunology Vol. 17; no. 2; pp. 140 - 149
• Main Authors: Decque, Adrien, Joffre, Olivier, Magalhaes, Joao G, Cossec, Jack-Christophe, Blecher-Gonen, Ronnie, Lapaquette, Pierre, Silvin, Aymeric, Manel, Nicolas, Joubert, Pierre-Emmanuel, Seeler, Jacob-Sebastian, Albert, Matthew L, Amit, Ido, Amigorena, Sebastian, Dejean, Anne
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2016; Nature Publishing Group
• Subjects: 13/31; 13/95; 38/61; 631/250/2502; 631/250/256; 631/250/262/2106; 64/110; 82/80; Analysis; Animals; Antiviral agents; Biological response modifiers; Biomedicine; Chromatin - genetics; Chromatin - metabolism; Cytokines; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Disease Resistance; Disease Susceptibility; Endotoxin shock; Endotoxins; Enhancer Elements, Genetic; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genetic Loci; Health aspects; Immunity, Innate; Immunology; Immunomodulation; Infectious Diseases; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - virology; Inflammation Mediators - metabolism; Influence; Innate immunity; Interferon; Interferon-beta - metabolism; Life Sciences; Lipopolysaccharides - immunology; Mice; Mice, Knockout; Myeloid cells; NF-κB protein; Protein Binding; Receptor, Interferon alpha-beta - metabolism; Regulatory Elements, Transcriptional; Risk factors; Shock, Septic - genetics; Shock, Septic - immunology; Shock, Septic - metabolism; Signal Transduction; SUMO protein; SUMO-1 Protein - metabolism; Sumoylation - genetics; Sumoylation - immunology; Toll-like receptors; Toll-Like Receptors - metabolism; Ubiquitin; β-Interferon; France; Gene regulation in immune cells; Inflammation; Pattern recognition receptors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3342

Sumolyation regulates wide-ranging biological processes, but its influence on innate immunity is unclear. Amigorena and colleagues show that sumoylation negatively regulates interferon-β expression and anti-viral immunity.
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.