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SNW1, a Novel Transcriptional Regulator of the NF-κB Pathway.

ABSTRACT: The nuclear factor kappa B (NF-κB) family of transcription factors plays a central role in coordinating the expression of genes that control inflammation, immune responses, cell proliferation, and a variety of other biological processes. In an attempt to identify novel regulators of this pathway, we performed whole-genome RNA interference (RNAi) screens in physiologically relevant human macrophages in response to lipopolysaccharide and tumor necrosis factor alpha (TNF-α). The top hit was SNW1, a splicing factor and transcriptional coactivator. SNW1 does not regulate the cytoplasmic components of the NF-κB pathway but complexes with the NF-κB heterodimer in the nucleus for transcriptional activation. We show that SNW1 detaches from its splicing complex (formed with SNRNP200 and SNRNP220) upon NF-κB activation and binds to NF-κB's transcriptional elongation partner p-TEFb. We also show that SNW1 is indispensable for the transcriptional elongation of NF-κB target genes such as the interleukin 8 (IL-8) and TNF genes. SNW1 is a unique protein previously shown to be involved in both splicing and transcription, and in this case, its role involves binding to the NF-κB-p-TEFb complex to facilitate transcriptional elongation of some NF-κB target genes.

SUBMITTER: Verma S

PROVIDER: S-EPMC6336138 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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SNW1, a Novel Transcriptional Regulator of the NF-κB Pathway.

Verma Suneer S De Jesus Paul P Chanda Sumit K SK Verma Inder M IM

Molecular and cellular biology 20190116 3

The nuclear factor kappa B (NF-κB) family of transcription factors plays a central role in coordinating the expression of genes that control inflammation, immune responses, cell proliferation, and a variety of other biological processes. In an attempt to identify novel regulators of this pathway, we performed whole-genome RNA interference (RNAi) screens in physiologically relevant human macrophages in response to lipopolysaccharide and tumor necrosis factor alpha (TNF-α). The top hit was SNW1, a ...[more]

PMID: 30397075

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Project description:BackgroundMacrophages are required for development and tissue repair and protect against microbial attacks. In response to external signals, monocytes differentiate into macrophages, but our knowledge of changes that promote this transition at the level of mRNA processing, in particular mRNA polyadenylation, needs advancement if it is to inform new disease treatments. Here, we identify CFIm25, a well-documented regulator of poly(A) site choice, as a novel mediator of macrophage differentiation.MethodsCFIm25 expression was analyzed in differentiating primary human monocytes and monocytic cell lines. Overexpression and depletion experiments were performed to assess CFIm25's role in differentiation, NF-κB signaling, and alternative polyadenylation (APA). mRNA 3' end-focused sequencing was conducted to identify changes in poly(A) site use of genes involved in macrophage differentiation and function. Cell cycle markers, NF-κB pathway components, and their targets were examined. The role of CFIm25 in NF-κB signaling was further evaluated through chemical inhibition and knockdown of pathway regulators.ResultsCFIm25 showed a striking increase upon macrophage differentiation, suggesting it promotes this process. Indeed, CFIm25 overexpression during differentiation amplified the acquisition of macrophage characteristics and caused an earlier slowing of the cell cycle, a hallmark of this transition, along with APA-mediated downregulation of cyclin D1. The NF-κB signaling pathway plays a major role in maturation of monocytes to macrophages, and the mRNAs of null, TBL1XR1, and NFKB1, all positive regulators of NF-κB signaling, underwent 3'UTR shortening, coupled with an increase in the corresponding proteins. CFIm25 overexpression also elevated phosphorylation of the NF-κB-p65 transcription activator, produced an earlier increase in the NF-κB targets p21, Bcl-XL, ICAM1 and TNF-α, and resulted in greater resistance to NF-κB chemical inhibition. Knockdown of Tables 2 and TBL1XR1 in CFIm25-overexpressing cells attenuated these effects, reinforcing the mechanistic link between CFIm25-regulated APA and NF-κB activation. Conversely, depletion of CFIm25 hindered differentiation and led to lengthening of NFKB1, TAB2, and TBL1XR1 3' UTRs.ConclusionsOur study establishes CFIm25 as a key mediator of macrophage differentiation that operates through a coordinated control of cell cycle progression and NF-κB signaling. This linkage of mRNA processing and immune cell function also expands our understanding of the role of alternative polyadenylation in regulating cell signaling.

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SNW1, a Novel Transcriptional Regulator of the NF-κB Pathway.

Publications

SNW1, a Novel Transcriptional Regulator of the NF-κB Pathway.

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