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

Mol Cell Biol. 2019 Jan 16;39(3):e00415-18. doi: 10.1128/MCB.00415-18. Print 2019 Feb 1.

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.

Keywords: NF-κB; RNAi screen; transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation
  • Humans
  • Macrophages / metabolism
  • NF-kappa B / metabolism*
  • Nuclear Receptor Coactivators / genetics*
  • Nuclear Receptor Coactivators / metabolism*
  • Positive Transcriptional Elongation Factor B / metabolism
  • Promoter Regions, Genetic
  • Signal Transduction
  • THP-1 Cells
  • Transcription Factor RelA / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • Nuclear Receptor Coactivators
  • RELA protein, human
  • SNW1 protein, human
  • Transcription Factor RelA
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Positive Transcriptional Elongation Factor B