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C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival

M Buck1, V Poli, T Hunter

  • 1Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Molecular Cell
|October 31, 2001
PubMed

Insights

Liver injury activates hepatic stellate cells, leading to cirrhosis. C/EBPbeta phosphorylation on Thr(217) regulates cell apoptosis and survival, offering potential therapeutic targets for liver fibrosis.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cell Biology

Background:

  • Hepatic stellate cells (HSCs) are key drivers of liver fibrosis and cirrhosis upon activation by liver injury.
  • The transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a critical role in HSC activation and proliferation.

Purpose of the Study:

  • To investigate the role of C/EBPbeta phosphorylation at Threonine 217 (Thr(217)) in regulating HSC apoptosis and survival during liver injury.
  • To elucidate the mechanism by which C/EBPbeta phosphorylation affects caspase activation and cell fate.

Main Methods:

  • Utilized carbon tetrachloride (CCl(4)) to induce liver injury in wild-type and C/EBPbeta knockout or mutant mice.
  • Assessed RSK activation, C/EBPbeta phosphorylation, HSC proliferation, and apoptosis.
  • Performed in vivo and in vitro assays to examine the interaction of C/EBPbeta with procaspases 1 and 8 and their activation.

Main Results:

  • CCl(4) induced HSC proliferation in normal mice but apoptosis in C/EBPbeta deficient or non-phosphorylatable mutant mice.
  • Phosphorylated C/EBPbeta (PThr(217)) and a phosphomimetic mutant (Glu(217)) associated with procaspases 1 and 8, inhibiting their activation.
  • A specific tetrapeptide mimicking the phosphorylated site rescued C/EBPbeta deficient/mutant HSCs from apoptosis.

Conclusions:

  • C/EBPbeta phosphorylation at Thr(217) is crucial for HSC survival following liver injury.
  • This phosphorylation creates a functional inhibitory motif (K-Phospho-T(217)VD) that binds and inhibits caspases.
  • Targeting C/EBPbeta phosphorylation or its downstream effects presents a potential therapeutic strategy for liver fibrosis.

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