Stress-induced non-vesicular release of prothymosin-α initiated by an interaction with S100A13, and its blockade by caspase-3 cleavage

Cell Death Differ. 2010 Nov;17(11):1760-72. doi: 10.1038/cdd.2010.52. Epub 2010 May 14.


The nuclear protein prothymosin-α (ProTα), which lacks a signal peptide sequence, is released from neurons and astrocytes on ischemic stress and exerts a unique form of neuroprotection through an anti-necrotic mechanism. Ischemic stress-induced ProTα release is initiated by a nuclear release, followed by extracellular release in a non-vesicular manner, in C6 glioma cells. These processes are caused by ATP loss and elevated Ca²(+), respectively. S100A13, a Ca²(+)-binding protein, was identified to be a major protein co-released with ProTα in an immunoprecipitation assay. The Ca²(+)-dependent interaction between ProTα and S100A13 was found to require the C-terminal peptide sequences of both proteins. In C6 glioma cells expressing a Δ88-98 mutant of S100A13, serum deprivation caused the release of S100A13 mutant, but not of ProTα. When cells were administered apoptogenic compounds, ProTα was cleaved by caspase-3 to generate a C-terminal peptide-deficient fragment, which lacks the nuclear localization signal (NLS). However, there was no extracellular release of ProTα. All these results suggest that necrosis-inducing stress induces an extacellular release of ProTα in a non-vesicular manner, whereas apoptosis-inducing stress does not, owing to the loss of its interaction with S100A13, a cargo molecule for extracellular release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • Astrocytes / metabolism*
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytosol / metabolism
  • Glioma
  • Immunoblotting
  • Ischemia / metabolism*
  • Necrosis
  • Neurons / metabolism*
  • Nuclear Localization Signals
  • Nuclear Proteins / metabolism
  • Polymerase Chain Reaction
  • Protein Precursors / chemistry
  • Protein Precursors / metabolism*
  • Rats
  • S100 Proteins / chemistry
  • S100 Proteins / metabolism*
  • Signal Transduction
  • Stress, Physiological*
  • Thymosin / analogs & derivatives*
  • Thymosin / chemistry
  • Thymosin / metabolism


  • Nuclear Localization Signals
  • Nuclear Proteins
  • Protein Precursors
  • S100 Proteins
  • prothymosin alpha
  • Thymosin
  • Adenosine Triphosphate
  • Caspase 3