Abstract
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.
Highlights
The nuclear Factor -κB (NF-κB) signaling pathway can be activated by different TLR ligands, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), resulting in the recruitment of adaptor proteins such as myeloid differentiation primary response gene 88 (MyD88), receptor-interacting protein (RIP1), and TIR-domain-containing adapter-inducing interferon-β (TRIF)[5]
There are five members of the Nuclear factor κB (NF-κB) transcription factors: p50, p52, p65/RelA, c-Rel, and RelB proteins[3]. All of these proteins share an N-terminal Rel homology domain (RHD) that mediates DNA binding and homoand heterodimerization. p65/RelA, c-Rel, and RelB contain transcription activation domains (TADs). which are responsible for positively regulating the expression of downstream genes. p50 and p52, which lack TADs, mainly inhibit transcription, unless they are recruited by other coactivators or interaction with a TAD-containing NF-κB member[10]
We investigated the roles of LRRC family proteins in the regulation of NF-κB signaling by co-transfecting expression vectors for individual LRRC proteins with a NF-κB luciferase reporter and Flag-tagged MyD88, which can induce activation of NF-κBluc
Summary
The nuclear Factor -κB (NF-κB) signaling pathway can be activated by different TLR ligands, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), resulting in the recruitment of adaptor proteins such as myeloid differentiation primary response gene 88 (MyD88), receptor-interacting protein (RIP1), and TIR-domain-containing adapter-inducing interferon-β (TRIF)[5]. These proteins act on downstream tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) signaling molecules including TRAF6, TRAF3, TRAF2 and TRAF5, which synthesize multiple poly-ubiquitin chains on themselves or other molecules, and recruit TGF-beta-activated kinase 1 (TAK1) and IκB kinase (IKK) complex[6,7]. We demonstrated that LRRC25 functions as an inhibitor of NF-κB signaling by promoting p65/RelA for autophagy degradation
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