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Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination

Shuqin Zhan1, Guo-Qiang Cai, Anni Zheng

  • 1Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. shqzhan@hotmail.com

Biochimica Et Biophysica Acta
|November 25, 2010
PubMed

Insights

Tumor necrosis factor alpha (TNF-α) downregulates the Hypocretin system, impacting sleep and feeding behaviors. This study reveals TNF-α reduces Prepro-Hypocretin and HcrtR2 protein and mRNA levels.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Sleep Research

Background:

  • The Hypocretin (Orexin) system is crucial for regulating sleep/wake cycles and feeding behaviors.
  • Tumor necrosis factor alpha (TNF-α) is implicated in sleep regulation, but its effect on the Hypocretin system is unclear.

Purpose of the Study:

  • To investigate the hypothesis that TNF-α regulates the Hypocretin system.
  • To elucidate the molecular mechanisms by which TNF-α affects Hypocretin and its receptor.

Main Methods:

  • Utilized rat B35 neuroblastoma cells, overexpressing Prepro-Hypocretin and Hypocretin receptor 2 (HcrtR2).
  • Assessed changes in mRNA and protein levels of Prepro-Hypocretin and HcrtR2 upon TNF-α treatment.
  • Investigated mRNA half-life and protein degradation pathways, including ubiquitination.

Main Results:

  • TNF-α significantly down-regulated Prepro-Hypocretin mRNA (94%) and protein (93%) levels, decreasing mRNA half-life.
  • TNF-α reduced HcrtR2 protein levels by 86% via ubiquitination, without affecting HcrtR2 mRNA.
  • Downregulation of cIAP-1/-2 proteins blocked TNF-α-induced HcrtR2 ubiquitination.

Conclusions:

  • TNF-α impairs Hypocretin system function by reducing Prepro-Hypocretin and HcrtR2 levels.
  • The findings suggest a novel regulatory pathway for the Hypocretin system involving TNF-α.
  • This implicates TNF-α in the pathophysiology of Hypocretin-related sleep and feeding disorders.

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