Abstract
Proper expression of the transcription factor, Positive regulatory domain 1 (PRDM1), is required for maintaining homeostasis of human monocyte derived-dendritic cells (MO-DCs). The molecular mechanisms and gene targets of PRDM1 in B and T lymphocytes have been identified. However, the function of PRDM1 in dendritic cells (DCs) remains unclear. We investigate co-regulators of PRDM1 in MO-DCs identified by mass spectrometry (MS) and co-immunoprecipitation (Co-IP). Notably, non-POU domain-containing octamer-binding protein (NonO) was found to be a PRDM1 binding protein in the nucleus of MO-DCs. NonO is recruited to the PRDM1 binding site in the promoter region of IL-6. Knockdown of NonO expression by siRNA lessened suppression of IL-6 promoter activity by PRMD1 following LPS stimulation. While NonO binding to PRDM1 was observed in human myeloma cell lines, an effect of NonO on IL-6 expression was not observed. Thus, loss of NonO interrupted the inhibitory effect of PRDM1 on IL-6 expression in MO-DCs, but not plasma cells. Moreover, MO-DCs with low expression of PRDM1 or NonO induce an increased number of IL-21-producing TFH-like cells in vitro. These data suggest that low level of PRDM1 and NonO lead to enhanced activation of MO-DCs and the regulation of MO-DC function by PRDM1 is mediated through cell lineage-specific mechanisms.
Highlights
Positive regulatory domain 1 (PRDM1, named BLIMP1) was identified as a repressor of interferon beta (IFN-β) gene expression in humans and mice [1, 2]
PRDM1 is a transcription factor that is expressed in multiple immune cells including myeloid cells [22, 35, 36]
It is involved in immune homeostasis and an insufficient level of PRDM1 in dendritic cells (DCs) leads to a breakdown in immune tolerance in mice [11]
Summary
Positive regulatory domain 1 (PRDM1, named BLIMP1) was identified as a repressor of interferon beta (IFN-β) gene expression in humans and mice [1, 2]. The immunological function of PRDM1 was first identified in B lymphocytes. Expression of PRDM1 is strongly induced in post-germinal center B cells committed to plasma cell (PC) differentiation [5, 6]. In PCs, PRDM1 acts as a master transcription factor through positive regulation of genes involved in plasmablast (PB) and PC function, and the absence of PRDM1 in B cells in mice leads to a lack of PC with hypoimmunoglobulinemia despite normal B cell memory responses [7,8,9]. Genome-wide association studies (GWAS) have identified polymorphisms in PRDM1 that are associated with autoimmune diseases. Single nucleotide polymorphisms (SNPs) predisposing to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are located in the intergenic
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