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

TY - JOUR

T1 - PKCα-LSD1-NF-κB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response

AU - Kim, Dongha

AU - Nam, Hye Jin

AU - Lee, Wonhwa

AU - Yim, Hwa Young

AU - Ahn, Jun-Yeong

AU - Park, Se Won

AU - Shin, Hi-Jai R

AU - Yu, Reynold

AU - Won, Kyoung-Jae

AU - Bae, Jong-Sup

AU - Kim, Keun Il

AU - Baek, Sung Hee

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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. The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Using a phosphorylation-defective knockin mouse model of LSD1, Kim et al. demonstrate that the PKCα-LSD1-NF-κB axis is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be powerful therapeutic strategy for systemic inflammatory diseases.

AB - 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. The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Using a phosphorylation-defective knockin mouse model of LSD1, Kim et al. demonstrate that the PKCα-LSD1-NF-κB axis is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be powerful therapeutic strategy for systemic inflammatory diseases.

U2 - 10.1016/j.molcel.2018.01.002

DO - 10.1016/j.molcel.2018.01.002

M3 - Journal article

C2 - 29395062

SN - 1097-2765

VL - 69

SP - 398-411.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -