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PMID:22863753

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Citation

Schneider, M, Zimmermann, AG, Roberts, RA, Zhang, L, Swanson, KV, Wen, H, Davis, BK, Allen, IC, Holl, EK, Ye, Z, Rahman, AH, Conti, BJ, Eitas, TK, Koller, BH and Ting, JP (2012) The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat. Immunol. 13:823-31

Abstract

Several members of the NLR family of sensors activate innate immunity. In contrast, we found here that NLRC3 inhibited Toll-like receptor (TLR)-dependent activation of the transcription factor NF-κB by interacting with the TLR signaling adaptor TRAF6 to attenuate Lys63 (K63)-linked ubiquitination of TRAF6 and activation of NF-κB. We used bioinformatics to predict interactions between NLR and TRAF proteins, including interactions of TRAF with NLRC3. In vivo, macrophage expression of Nlrc3 mRNA was diminished by the administration of lipopolysaccharide (LPS) but was restored when cellular activation subsided. To assess biologic relevance, we generated Nlrc3(-/-) mice. LPS-treated Nlrc3(-/-) macrophages had more K63-ubiquitinated TRAF6, nuclear NF-κB and proinflammatory cytokines. Finally, LPS-treated Nlrc3(-/-) mice had more signs of inflammation. Thus, signaling via NLRC3 and TLR constitutes a negative feedback loop. Furthermore, prevalent NLR-TRAF interactions suggest the formation of a 'TRAFasome' complex.

Links

PubMed PMC3721195 Online version:10.1038/ni.2378

Keywords

Amino Acid Sequence; Animals; Feedback, Physiological; HEK293 Cells; Humans; Macrophages/immunology; Macrophages/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; NF-kappa B/immunology; NF-kappa B/metabolism; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled/immunology; Receptors, G-Protein-Coupled/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/immunology; TNF Receptor-Associated Factor 6/immunology; TNF Receptor-Associated Factor 6/metabolism; Toll-Like Receptors/immunology; Toll-Like Receptors/metabolism

Significance

Annotations

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

MOUSE:TRAF6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q5DU56

F

Seeded From UniProt

complete

MOUSE:TRAF6

acts_upstream_of_or_within

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444070

P

  • regulates_o_occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:NLRC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P70196

F

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000576)

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108072

P

  • regulates_o_occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:TRAF6

acts_upstream_of_or_within

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444070

P

regulates_o_occurs_in:(CL:0000235)

Seeded From UniProt

complete

HUMAN:NLRC3

involved_in

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRC3

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000314:

P

Overexpression of NLRC3 led to decreased production of TNF through the MyD88 pathway of Hek293 T cells as shown in figure 1b.

complete
CACAO 9178

HUMAN:NLRC3

GO:0032715: negative regulation of interleukin-6 production

ECO:0000314:

P

Figure 1d the second graph indicate that with overexpressed NLRC3 this decreases production of IL-6 in HEK293 t cells.

complete
CACAO 9179

HUMAN:NLRC3

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000315:

P

Figure 1c shows when NLRC3 is not expressed in HEK293 T cells then the production of TNF in these cells increases indicating that NLRC3 negatively regulates TNF production.

complete
CACAO 9180

HUMAN:NLRC3

GO:0032715: negative regulation of interleukin-6 production

ECO:0000315:

P

Figure 1c shows that when NLRC3 is not expressed concentrations of IL-6 increase indicating that NLRC3 negatively regulates IL-6 production in HEK293 T cells.

complete
CACAO 9181

HUMAN:NLRC3

involved_in

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRC3

involved_in

GO:0032715: negative regulation of interleukin-6 production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRC3

involved_in

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRC3

involved_in

GO:0032715: negative regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108072

P

regulates_o_occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0000576)

Seeded From UniProt

complete

MOUSE:NLRC3

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000315:

P

With knockout mice, Figure 4c graph 1 shows that with stimulation of the TLR on the cell that there is an increased production of the TNF when compared to the WT.

complete
CACAO 9191

MOUSE:NLRC3

GO:0032715: negative regulation of interleukin-6 production

ECO:0000315:

P

Figure 4c graph 2. In knockout mice of the NLCR3 protein then in response to stimulation of TLR then there is an increased amount of IL-6 made when compared to the WT cell.

complete
CACAO 9192

MOUSE:NLRC3

GO:0032695: negative regulation of interleukin-12 production

ECO:0000315:

P

Figure 4c graph 4. With knockout mice of NLRC3 protein when TLR was stimulated there was an increased production of IL-12 when compared to the WT thus indicating that NLRC3 negatively regulates the IL-12 production.

complete
CACAO 9193

MOUSE:NLRC3

GO:0032691: negative regulation of interleukin-1 beta production

ECO:0000315:

P

With knockdown of protein NLRC3 in mice, figure 4c graph 3 indicates that these mice upon TLR stimulation resulted in increased production of IL-1 beta when compared to the WT mice TLR response. This indicates that NLRC3 negatively regulates the production if IL-1 beta.

complete
CACAO 9194

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0032496: response to lipopolysaccharide

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5439971

P

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0031396: regulation of protein ubiquitination

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5439971

P

Seeded From UniProt

complete

MOUSE:NLRC3

acts_upstream_of_or_within

GO:0031396: regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032720: negative regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032715: negative regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032695: negative regulation of interleukin-12 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032691: negative regulation of interleukin-1 beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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