Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA.
The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. ... Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.
Mesh Terms:
Amino Acid Motifs, Animals, Binding Sites, Breast Neoplasms, Carrier Proteins, Cells, Cultured, Cytokines, DNA-Binding Proteins, Female, Fibroblasts, Humans, I-kappa B Kinase, I-kappa B Proteins, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, NF-kappa B, Peptidylprolyl Isomerase, Phosphorylation, Protein Binding, Protein Subunits, Protein-Serine-Threonine Kinases, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Transcription Factor RelA, Transcriptional Activation, Ubiquitin
Amino Acid Motifs, Animals, Binding Sites, Breast Neoplasms, Carrier Proteins, Cells, Cultured, Cytokines, DNA-Binding Proteins, Female, Fibroblasts, Humans, I-kappa B Kinase, I-kappa B Proteins, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, NF-kappa B, Peptidylprolyl Isomerase, Phosphorylation, Protein Binding, Protein Subunits, Protein-Serine-Threonine Kinases, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Transcription Factor RelA, Transcriptional Activation, Ubiquitin
Mol. Cell
Date: Dec. 01, 2003
PubMed ID: 14690596
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