Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA

Mol Cell. 2003 Dec;12(6):1413-26. doi: 10.1016/s1097-2765(03)00490-8.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Knockout
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Subunits / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factor RelA
  • Transcriptional Activation
  • Ubiquitin / metabolism*

Substances

  • Carrier Proteins
  • Cytokines
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nfkbia protein, mouse
  • Protein Subunits
  • Repressor Proteins
  • SOCS1 protein, human
  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factor RelA
  • Ubiquitin
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse