PKCα-LSD1-NF-κB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response

Research output: Contribution to journalJournal articleResearchpeer-review

  • Dongha Kim
  • Hye Jin Nam
  • Wonhwa Lee
  • Hwa Young Yim
  • Jun-Yeong Ahn
  • Se Won Park
  • Hi-Jai R Shin
  • Reynold Yu
  • Won, Kyoung Jae
  • Jong-Sup Bae
  • Keun Il Kim
  • Sung Hee Baek

The inflammatory response mediated by nuclear factor κB (NF-κB) signaling is essential for host defense against pathogens. Although the regulatory mechanism of NF-κB signaling has been well studied, the molecular basis for epigenetic regulation of the inflammatory response is poorly understood. Here we identify a new signaling axis of PKCα-LSD1-NF-κB, which is critical for activation and amplification of the inflammatory response. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. LSD1 phosphorylation is required for p65 binding and facilitates p65 demethylation, leading to enhanced stability. In vivo genetic analysis using Lsd1SA/SA mice with ablation of LSD1 phosphorylation and chemical approaches in wild-type mice with inhibition of PKCα or LSD1 activity show attenuated sepsis-induced inflammatory lung injury and mortality. Together, we demonstrate that the PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be a powerful therapeutic strategy for systemic inflammatory diseases, including sepsis.

Original languageEnglish
JournalMolecular Cell
Volume69
Issue number3
Pages (from-to)398-411.e6
ISSN1097-2765
DOIs
Publication statusPublished - 1 Feb 2018
Externally publishedYes

ID: 199325445