Stress-induced non-vesicular extracellular release of complex of Ca^<2+>-binding proteins

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The nuclear protein prothymosin-α (ProT_α), which lacks a signal peptide sequence, is release from neurons and astrocytes on ischemic stress and exerts a unique form of neuroprotection through an anti-necrotic mechanism. Ischemic stress-induced ProT_α release is initiated by a nuclear release due to ATP loss, followed by extracellular release in a non-vesicular manner. S100A13, a Ca^<2+>-biniding protein, was identified to be a major protein co-released with ProT_α. The Ca^<2+>-dependent inteaction between ProT_α and S100A13 was found to require the C-terminal peptide sequences of both proteins. Under apoptotic condition, ProT_α was cleaved by casase-3 to generate a C-terminal peptide-deficient fragment, which lacks the nuclear localization signal. However, there was no extracellular release of ProT_α. These results suggest that necrosis-inducing stress induces an extracellula release of ProT_α in a non-vesicular maner, whereas apoptosis-inducing stress does not, owing to the loss of its interaction with S100A13, a cargo molecule for extracellular release.