title: The small ubiquitin-like modifier-deconjugating enzyme sentrin-specific peptidase 1 switches IFN regulatory factor 8 from a repressor to an activator during macrophage activation.
abstract: Macrophages, when activated by IFN-γ and TLR signaling, elicit innate immune responses. IFN regulatory factor 8 (IRF8) is a transcription factor that facilitates macrophage activation and innate immunity. We show that, in resting macrophages, some IRF8 is conjugated to small ubiquitin-like modifiers (SUMO) 2/3 through the lysine residue 310. SUMO3-conjugated IRF8 failed to induce IL12p40 and other IRF8 target genes, consistent with SUMO-mediated transcriptional repression reported for other transcription factors. SUMO3-conjugated IRF8 showed reduced mobility in live nuclei and bound poorly to the IL12p40 gene. However, macrophage activation caused a sharp reduction in the amount of SUMOylated IRF8. This reduction coincided with the induction of a deSUMOylating enzyme, sentrin-specific peptidase 1 (SENP1), in activated macrophages. In transfection analysis, SENP1 removed SUMO3 from IRF8 and enhanced expression of IL12p40 and other target genes. Conversely, SENP1 knockdown repressed IRF8 target gene expression. In parallel with IRF8 deSUMOylation, macrophage activation led to the induction of proteins active in the SUMO pathway and caused a global shift in nuclear protein SUMOylation patterns. Together, the IRF8 SUMO conjugation/deconjugation switch is part of a larger transition in SUMO modifications that takes place upon macrophage activation, serving as a mechanism to trigger innate immune responses.
authors.affiliation: Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chang
authors.forename: Songxiao
authors.initials: S
authors.lastname: Xu
authors.forename: Prafullakumar
authors.initials: P
authors.lastname: Tailor
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kanno
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism* / Q000502:physiology; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000276:immunology; D012097:Repressor Proteins / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation / Q000276:immunology; D014452:Ubiquitins / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D008239:Lysine; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014452:Ubiquitins; D000099185:Interferon Regulatory Factor-8; C117909:SUMO2 protein, human; C515972:SUMO2 protein, mouse; C492189:SUMO3 protein, human; C117908:Sumo3 protein, mouse; C404512:SENP1 protein, human; C501974:Senp1 protein, mouse