Role of NonO-histone interaction in TNFalpha-suppressed prolyl-4-hydroxylase alpha1

Biochim Biophys Acta. 2008 Aug;1783(8):1517-28. doi: 10.1016/j.bbamcr.2008.03.011. Epub 2008 Mar 29.


Inflammation is a key process in cardiovascular diseases. The extracellular matrix (ECM) of the vasculature is a major target of inflammatory cytokines, and TNFalpha regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNFalpha-induced suppression of prolyl-4 hydroxylase alpha1 (P4Halpha1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNFalpha activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNFalpha response element in the P4Halpha1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4Halpha1 promoter. Furthermore, we found that TNFalpha oxidized DJ-1, which may be essential for the NonO-P4Halpha1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNFalpha-induced NonO-P4Halpha1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cells, Cultured
  • DNA-Binding Proteins
  • Gene Expression Regulation, Enzymologic*
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase 4 / metabolism
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / metabolism
  • Nuclear Matrix-Associated Proteins / metabolism*
  • Octamer Transcription Factors / metabolism*
  • Oncogene Proteins
  • Procollagen-Proline Dioxygenase / biosynthesis
  • Procollagen-Proline Dioxygenase / genetics*
  • Protein Deglycase DJ-1
  • RNA-Binding Proteins / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • DNA-Binding Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • NONO protein, human
  • Nuclear Matrix-Associated Proteins
  • Octamer Transcription Factors
  • Oncogene Proteins
  • RNA-Binding Proteins
  • Tumor Necrosis Factor-alpha
  • P4HA1 protein, human
  • Procollagen-Proline Dioxygenase
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase 4
  • PARK7 protein, human
  • Protein Deglycase DJ-1