Novel receptor mechanisms of prothymosin alpha, a neuroprotective DAMPs molecule

[Speaker] Ryusei Iwamoto:1
[Co-author] Shiori Maeda:1, Hiroshi Ueda:1
1:Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Japan

Nuclear protein, prothymosin alpha (ProTa), discovered as a neuronal necrosis-inhibitor from the conditioned medium of serum-free starving culture of embryonic cortical neurons (JCB 2007), is found to have various neuroprotective actions. Under the neuronal necrotic condition, ProTa extracellularly released in a non-classical and non-vesicular mechanism through S100A13 and SNARE proteins, inhibits necrosis by a rescue of intracellular ATP levels due to a plasma membrane translocation of glucose transporters, through putative Gi-coupled receptor and PKC mechanisms. ProTa also causes an activation of caspase 3, an apoptosis mechanism, through similar intracellular signaling mechanisms. But the caspase 3 activation seems to delay the necrosis by degrading PARP, which consumes abundant ATP. By the affinity cross-link strategy we identified some species of ecto-ATPase would be a candidate for the ProTa binding. Further studies ProTa is found to increase the extracellular levels of ATP, which is in turn converted to ADP or adenosine, possibly followed by an activation of Gi-coupled receptor P2Y12/13 or adenosine A1. Some of these mechanisms were confirmed by in vitro studies using recombinant ecto-ATPase and by in vivo studies using neutralizing antibodies against ecto-ATPase. ProTa also shows neuroprotective actions through TLR4 activation. Unique mechanism was observed in the finding that ProTa drives only anti-inflammatory TRIF-IRF3 mechanisms, but not pro-inflammatory MyD88-NF-kappaB mechanisms.
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