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PMID:20547752

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Citation

Sharif-Askari, E, Vassen, L, Kosan, C, Khandanpour, C, Gaudreau, MC, Heyd, F, Okayama, T, Jin, J, Rojas, ME, Grimes, HL, Zeng, H and Möröy, T (2010) Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65. Mol. Cell. Biol. 30:3929-42

Abstract

Endotoxin (bacterial lipopolysaccharide [LPS]) causes fatal septic shock via the Toll-like receptor 4 (TLR-4) protein present on innate immunity effector cells, which activates nuclear factor kappa B (NF-kappaB), inducing proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha). An early step in this process involves nuclear sequestration of the p65-RelA NF-kappaB subunit, enabling transcriptional activation of target inflammatory cytokine genes. Here, we analyzed the role of the nuclear zinc finger protein Gfi1 in the TLR response using primary bone marrow-derived macrophages. We show that upon LPS stimulation, expression of Gfi1 is induced with kinetics similar to those of nuclear translocation of p65 and that Gfi1 interacts with p65 and inhibits p65-mediated transcriptional transactivation by interfering with p65 binding to target gene promoter DNA. Gfi1-deficient macrophages show abnormally high mRNA levels of the TNF-alpha gene and many other p65 target genes and a higher rate of TNF promoter occupancy by p65 than wild-type cells after LPS stimulation, suggesting that Gfi1 functions as an antagonist of NF-kappaB activity at the level of promoter binding. Our findings identify a new function of Gfi1 as a general negative regulator of the endotoxin-initiated innate immune responses, including septic shock and possibly other severe inflammatory diseases.

Links

PubMed PMC2916436 Online version:10.1128/MCB.00087-10

Keywords

Animals; Base Sequence; Cell Line; DNA/genetics; DNA/metabolism; DNA Primers/genetics; DNA-Binding Proteins/antagonists & inhibitors; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Humans; Immunity, Innate/drug effects; Inflammation/etiology; Inflammation/immunology; Inflammation/metabolism; Lipopolysaccharides/toxicity; Macrophages/immunology; Macrophages/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; RNA, Messenger/genetics; RNA, Messenger/metabolism; Shock, Septic/etiology; Shock, Septic/immunology; Shock, Septic/metabolism; Signal Transduction; Toll-Like Receptors/metabolism; Transcription Factor RelA/antagonists & inhibitors; Transcription Factors/antagonists & inhibitors; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Transcriptional Activation; Tumor Necrosis Factor-alpha/genetics; Zinc Fingers

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NFKB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04206

F

Seeded From UniProt

complete

MOUSE:GFI1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1

involved_in

GO:0032088: negative regulation of NF-kappaB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19838

F

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99684

F

Seeded From UniProt

complete

MOUSE:TF65

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99684

F

Seeded From UniProt

complete

HUMAN:GFI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04207

F

Seeded From UniProt

complete

HUMAN:GFI1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GFI1

involved_in

GO:0034121: regulation of toll-like receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GFI1

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GFI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04206

F

Seeded From UniProt

complete

MOUSE:TF65

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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