Stress-induced non-vesicular release of prothymosin-α initiated by an interaction with S100A13, and its blockade by caspase-3 cleavage.
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.
Matsunaga
H
H
Department of Molecular Medicinal Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan.
Ueda
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005910:Glioma; D015151:Immunoblotting; D007511:Ischemia / Q000378:metabolism*; D009336:Necrosis; D009474:Neurons / Q000378:metabolism*; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D009418:S100 Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D013947:Thymosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011498:Protein Precursors; D009418:S100 Proteins; C040782:prothymosin alpha; D013947:Thymosin; D000255:Adenosine Triphosphate; D053148:Caspase 3