Inflammation is considered a fundamental host defense mechanism and, when aberrantly activated, contributes to a host of human diseases. Previously we have reported that the transcriptional regulator megakaryocytic leukemia 1 (MKL1) plays a role programming cellular inflammatory response by modulating NF-κB activity. Here we report that MKL1 was acetylated in vivo and pro-inflammatory stimuli (TNF-α and LPS) augmented MKL1 acetylation accompanying increased MKL1 binding to NF-κB target promoters. Further analysis revealed that the lysine acetyltransferase PCAF mediated MKL1 acetylation: TNF-α and LPS promoted the interaction between MKL1 and PCAF whereas depletion of PCAF abrogated the induction of MKL1 acetylation by TNF-α and LPS. Acetylation of MKL1 was necessary for MKL1 to activate the transcription of pro-inflammatory genes because mutation of four conserved lysine residues in MKL1 attenuated its capacity as a trans-activator of NF-κB target genes. Mechanistically, MKL1 acetylation served to promote MKL1 nuclear enrichment, to enhance the MKL1-NF-κB interaction, and to stabilize the binding of MKL1 on target promoters. In conclusion, our data unveil an important pathway that contributes to the transcriptional regulation of inflammatory response.
Keywords: Acetylation; MKL1; PCAF; Transcriptional regulation.
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