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Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages.

Publication ,  Journal Article
Gao, C; Guo, H; Mi, Z; Grusby, MJ; Kuo, PC
Published in: J Immunol
February 1, 2007

In systemic inflammation induced by endotoxin (LPS), the macrophage produces the majority of the circulating NO metabolites. However, while the molecular pathways which up-regulate iNOS expression have been extensively studied in the macrophage, little is known of the parallel counterregulatory pathways which repress or inhibit macrophage iNOS expression. Using both in vivo and in vitro murine models of endotoxin (LPS) stimulation, we have previously demonstrated that NO feedback inhibits its own synthesis by increasing transcription of osteopontin (OPN), a potent transrepressor of inducible NO synthase expression. In this current study, using a system of LPS-treated RAW264.7 macrophages, we go on to demonstrate that OPN increases STAT1 ubiquitination and subsequent 26s proteasome-mediated degradation to inhibit STAT1 dependent iNOS promoter activity, transcription, and protein expression. In addition, we identify STAT-interacting LIM protein as the critical STAT ubiquitin E3 ligase critical for STAT1 degradation in this setting. OPN has not been linked previously to STAT1 degradation. This regulation of STAT1 degradation underlies OPN's effect as an inhibitor of iNOS gene transcription. These are novel findings and define OPN as a unique and as yet, poorly characterized, transactivator of STAT1 degradation by the ubiquitin-proteasome system.

Duke Scholars

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

February 1, 2007

Volume

178

Issue

3

Start / End Page

1870 / 1881

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Ubiquitin
  • Transcription, Genetic
  • STAT1 Transcription Factor
  • Osteopontin
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mice
  • Macrophages
  • Lipopolysaccharides
 

Citation

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Gao, C., Guo, H., Mi, Z., Grusby, M. J., & Kuo, P. C. (2007). Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages. J Immunol, 178(3), 1870–1881. https://doi.org/10.4049/jimmunol.178.3.1870
Gao, Chengjiang, Hongtao Guo, Zhiyong Mi, Michael J. Grusby, and Paul C. Kuo. “Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages.J Immunol 178, no. 3 (February 1, 2007): 1870–81. https://doi.org/10.4049/jimmunol.178.3.1870.
Gao C, Guo H, Mi Z, Grusby MJ, Kuo PC. Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages. J Immunol. 2007 Feb 1;178(3):1870–81.
Gao, Chengjiang, et al. “Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages.J Immunol, vol. 178, no. 3, Feb. 2007, pp. 1870–81. Pubmed, doi:10.4049/jimmunol.178.3.1870.
Gao C, Guo H, Mi Z, Grusby MJ, Kuo PC. Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages. J Immunol. 2007 Feb 1;178(3):1870–1881.

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

February 1, 2007

Volume

178

Issue

3

Start / End Page

1870 / 1881

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Ubiquitin
  • Transcription, Genetic
  • STAT1 Transcription Factor
  • Osteopontin
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mice
  • Macrophages
  • Lipopolysaccharides