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Acetylation of MKL1 by PCAF regulates pro-inflammatory transcription

Liming Yu1, Zilong Li1, Mingming Fang2

  • 1Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.

Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms
|June 3, 2017
PubMed

Insights

The transcriptional regulator megakaryocytic leukemia 1 (MKL1) is acetylated by PCAF in response to inflammatory stimuli. This acetylation enhances MKL1

Area of Science:

  • Cellular biology
  • Molecular mechanisms of inflammation
  • Transcriptional regulation

Background:

  • Inflammation is a critical defense mechanism implicated in various human diseases.
  • Megakaryocytic leukemia 1 (MKL1) is a transcriptional regulator involved in cellular inflammatory responses by modulating NF-κB activity.

Purpose of the Study:

  • To investigate the role of MKL1 acetylation in regulating inflammatory gene transcription.
  • To identify the specific enzymes and mechanisms involved in MKL1 acetylation and its functional consequences.

Main Methods:

  • In vivo studies assessing MKL1 acetylation.
  • Treatment with pro-inflammatory stimuli (TNF-α and LPS).
  • Analysis of MKL1 binding to NF-κB target promoters.
  • Investigation of the role of lysine acetyltransferase PCAF.
  • Site-directed mutagenesis of MKL1 lysine residues.
  • Assessment of MKL1 nuclear localization and interaction with NF-κB.

Main Results:

  • Pro-inflammatory stimuli (TNF-α and LPS) increase MKL1 acetylation and promoter binding.
  • PCAF mediates MKL1 acetylation, with its interaction with MKL1 enhanced by inflammatory stimuli.
  • Depletion of PCAF inhibits TNF-α and LPS-induced MKL1 acetylation.
  • Acetylation of MKL1 is essential for its trans-activation of NF-κB target genes.
  • MKL1 acetylation promotes nuclear enrichment, enhances MKL1-NF-κB interaction, and stabilizes promoter binding.

Conclusions:

  • MKL1 acetylation by PCAF is a key regulatory mechanism in the inflammatory response.
  • This acetylation pathway enhances the transcriptional activity of MKL1 on pro-inflammatory genes.
  • The findings reveal a novel mechanism contributing to the transcriptional control of inflammation.
Keywords:
AcetylationMKL1PCAFTranscriptional regulation

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