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MST1 promotes apoptosis through phosphorylation of histone H2AX

Weihong Wen1, Feng Zhu, Jishuai Zhang

  • 1Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.

The Journal of Biological Chemistry
|October 6, 2010
PubMed

Insights

Mammalian STE20-like kinase 1 (MST1) activates apoptosis by phosphorylating histone H2AX. This phosphorylation drives chromatin condensation and DNA fragmentation during programmed cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mammalian STE20-like kinase 1 (MST1) is a key enzyme activated during apoptosis.
  • The precise mechanisms by which MST1 induces apoptotic morphological changes, like chromatin condensation, remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of MST1 in apoptotic chromatin condensation.
  • To identify the direct molecular targets of MST1 during apoptosis.

Main Methods:

  • In vitro kinase assays to assess MST1's phosphorylation activity on histone H2AX.
  • Western blot analysis and immunoprecipitation to detect MST1-H2AX interactions and phosphorylation.
  • Experiments using MST1 and H2AX mutants, caspase inhibitors, and gene knockdown in cell lines (Jurkat, HEK293, HeLa).

Main Results:

  • MST1 directly phosphorylates histone H2AX at Ser-139, a key event in apoptosis.
  • MST1 and H2AX were shown to directly bind.
  • Cleaved MST1, activated by caspases, is responsible for H2AX phosphorylation during apoptosis, leading to chromatin condensation and DNA fragmentation.

Conclusions:

  • Histone H2AX is a direct substrate of MST1.
  • MST1-mediated H2AX phosphorylation is a critical mechanism for inducing apoptotic chromatin condensation and DNA fragmentation.

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