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.