Blimp-1/PRDM1 mediates transcriptional suppression of the NLR gene NLRP12/Monarch-1.
NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1(-/-) murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene.
Lord
Christopher A
CA
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Savitsky
David
D
Sitcheran
Raquel
R
Calame
Kathryn
K
Wright
Jo Rae
JR
Ting
Jenny Pan-Yun
JP
Williams
Kristi L
KL
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D020298:U937 Cells
D047908:Intracellular Signaling Peptides and Proteins; C476731:NLRP12 protein, human; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1