| First Author | Kim D | Year | 2018 |
| Journal | Mol Cell | Volume | 69 |
| Issue | 3 | Pages | 398-411.e6 |
| PubMed ID | 29395062 | Mgi Jnum | J:257693 |
| Mgi Id | MGI:6120034 | Doi | 10.1016/j.molcel.2018.01.002 |
| Citation | Kim D, et al. (2018) PKCalpha-LSD1-NF-kappaB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response. Mol Cell 69(3):398-411.e6 |
| abstractText | The inflammatory response mediated by nuclear factor kappaB (NF-kappaB) signaling is essential for host defense against pathogens. Although the regulatory mechanism of NF-kappaB 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 PKCalpha-LSD1-NF-kappaB, which is critical for activation and amplification of the inflammatory response. In response to excessive inflammatory stimuli, PKCalpha 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 Lsd1(SA/SA) mice with ablation of LSD1 phosphorylation and chemical approaches in wild-type mice with inhibition of PKCalpha or LSD1 activity show attenuated sepsis-induced inflammatory lung injury and mortality. Together, we demonstrate that the PKCalpha-LSD1-NF-kappaB 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. |
