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The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation.

ABSTRACT: The PI3K pathway plays a key role in B cell activation and is important for the differentiation of Ab producing plasma cells (PCs). Although much is known about the molecular mechanisms that modulate PI3K signaling in B cells, the transcriptional regulation of PI3K expression is poorly understood. In this study, we identify the zinc finger protein Zbtb18 as a transcriptional repressor that directly binds enhancer/promoter regions of genes encoding class I PI3K regulatory subunits, subsequently limiting their expression, dampening PI3K signaling and suppressing PC responses. Following activation, dividing B cells progressively downregulated Zbtb18, allowing gradual amplification of PI3K signals and enhanced development of PCs. Human Zbtb18 displayed similar expression patterns and function in human B cells, acting to inhibit development of PCs. Furthermore, a number of Zbtb18 mutants identified in cancer patients showed loss of suppressor activity, which was also accompanied by impaired regulation of PI3K genes. Taken together, our study identifies Zbtb18 as a repressor of PC differentiation and reveals its previously unappreciated function as a transcription modulator of the PI3K signaling pathway.

SUBMITTER: Xie B

PROVIDER: S-EPMC7980533 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation.

Xie Bin B Khoyratty Tariq E TE Abu-Shah Enas E F Cespedes Pablo P MacLean Andrew J AJ Pirgova Gabriela G Hu Zhiyuan Z Ahmed Ahmed A AA Dustin Michael L ML Udalova Irina A IA Arnon Tal I TI

Journal of immunology (Baltimore, Md. : 1950) 20210219 7

The PI3K pathway plays a key role in B cell activation and is important for the differentiation of Ab producing plasma cells (PCs). Although much is known about the molecular mechanisms that modulate PI3K signaling in B cells, the transcriptional regulation of PI3K expression is poorly understood. In this study, we identify the zinc finger protein Zbtb18 as a transcriptional repressor that directly binds enhancer/promoter regions of genes encoding class I PI3K regulatory subunits, subsequently l ...[more]

PMID: 33608456

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Project description:The heterotrophic marine microalgae Schizochytrium sp. is an important industrial producer of docosahexaenoic acid (DHA). Increased production of DHA and lipids in Schizochytrium sp. has been achieved by standard fermentation optimization and metabolic engineering methods; however, regulatory mechanisms for DHA and lipid biosynthesis remain unknown. In this study, the C2H2 zinc finger protein LipR was identified in Schizochytrium sp. ATCC 20888 by transcriptional analysis. Deletion of the lipR gene significantly (P < 0.001) increased production of total lipids and DHA by 33% and 48%, respectively. LipR repressed DHA and lipid production by directly inhibiting transcription of polyunsaturated fatty acid (PUFA) and fatty acid synthase (FAS) genes (pfa1, pfa2, pfa3, and fas). Specific binding of LipR to 9-bp recognition sequence 5'-(C/A)(A/G)CCATCTT-3' in upstream regions of target genes was demonstrated by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. Expression of several key genes (acc, acl, ampD, fabD, mae, zwf, and dga1) related to levels of precursors and NADPH, and to triacylglycerol storage rate, were also directly repressed by LipR. Our findings, taken together, indicate that the evolutionarily unique regulator LipR is an essential repressor of DHA and saturated fatty acid biosynthesis in Schizochytrium sp. IMPORTANCE Regulatory mechanisms for DHA and saturated fatty acid biosynthesis in the heterotrophic marine microalgae Schizochytrium sp. are unclear. We demonstrate here that deletion of the gene (lipR) encoding the C2H2 zinc finger protein LipR promotes DHA and saturated fatty acid production in this genus. LipR acts as a key repressor of such production by binding to 9-bp consensus sequence 5'-(C/A)(A/G)CCATCTT-3' in the upstream regions of polyunsaturated fatty acid and fatty acid synthase genes (pfa1, pfa2, pfa3, and fas), and genes related to levels of precursors and NADPH (acc, acl, ampD, fabD, mae, and zwf), and to triacylglycerol storage rate (dga1). This is the first demonstration that a regulator inhibits synthesis of DHA and lipids in Schizochytrium sp. by directly controlling transcription of PUFA synthase and fas genes. Manipulation of the lipR gene provides a potential strategy for enhancing accumulation of polyunsaturated fatty acids and lipids in thraustochytrids.

Dataset Information

The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation.

Publications

The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation.

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