Abstract

The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding β-transducin repeat-containing protein (β-TrCP) to IκBα results inhibition of β-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation.

Highlights

  • The nuclear factor kappa B (NF-kB), an important early transcription regulator, is involved in various cellular responses to stimuli, such as ultraviolet irradiation, heavy metals, cytokines, free radicals, and microbial infection [1]

  • We found that the TNFatriggered nuclear translocation of p65 was significantly restricted by TRIM67 expression (Table S1)

  • By the analysis of p65 nuclear translocation events, we found that 95% of TRIM67-expressing cells showed p65 cytoplasmic retention with the treatment of TNFa (Figure 1B)

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Summary

Introduction

The nuclear factor kappa B (NF-kB), an important early transcription regulator, is involved in various cellular responses to stimuli, such as ultraviolet irradiation, heavy metals, cytokines, free radicals, and microbial infection [1]. NF-kB plays a crucial role in many cellular events, including inflammation, cancer, cell growth, apoptosis, and immunity [2–4]. The NF-kB complex is maintained in the cytoplasm in an inactive form through inhibitor IkB proteins. IkB proteins are phosphorylated by IkB kinases (IKK) complex such as IKKa, IKKb. The phosphorylated IkB proteins are degraded by 26S-proteasome pathways [5–7]. With the degradation of IkB proteins, NF-kB is freed to be transported into the nucleus, where it activates the transcription of a large number of genes [3]

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