LRRC25 Functions as an Inhibitor of NF-κB Signaling Pathway by Promoting p65/RelA for Autophagic Degradation

• Published in: Scientific reports Vol. 7; no. 1; pp. 13448 - 12
• Main Authors: Feng, Yanchun, Duan, Tianhao, Du, Yang, Jin, Shouheng, Wang, Mingjun, Cui, Jun, Wang, Rong-Fu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.10.2017; Nature Publishing Group
• Subjects: 14; 14/1; 14/34; 14/63; 38/109; 38/77; 631/250/262/2106/2108; 631/80/86; 82; 82/1; 82/80; Autophagy; Cytokines; Ectopic expression; Homology; Humanities and Social Sciences; Immune response; Inflammation; Innate immunity; Leucine; Molecular modelling; multidisciplinary; NF-κB protein; Phagocytosis; RelA protein; Science; Science (multidisciplinary); Signal transduction; Transcription factors
• DOI: 10.1038/s41598-017-12573-3
• ISSN: 2045-2322

Nuclear factor κB (NF-κB) is a family of critical transcription factors that play a critical role in innate immune responses and inflammation, yet the molecular mechanisms responsible for its tight regulation is not fully understood. In this study, we identified LRRC25, a member of leucine-rich repeat (LRR)-containing protein family, as a negative regulator in the NF-κB signaling pathway. Ectopic expression of LRRC25 impaired NF-κB activation, whereas knockout of LRRC25 potentiated NF-κB activation and enhanced the production of inflammatory cytokines. Further study demonstrated that the LRR domain of LRRC25 interacted with the Rel Homology domain (RHD) of p65/RelA and promotes the degradation of p65/RelA. Furthermore, LRRC25 enhanced the interaction between p65/RelA and cargo receptor p62, thus facilitating the degradation of p65/RelA through autophagy pathway. Our study has not only identified LRRC25 as a novel inhibitor of NF-κB signaling pathway, but also uncovers a new mechanism of crosstalk between NF-κB signaling and autophagy pathways.