Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out
Nuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell death mode switch in serum-starving or ischemic/reperfusion models in vitro and in vivo. Underlying receptor mechanisms include Toll-l...
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MDPI AG
2023-06-01
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author | Hiroshi Ueda |
author_facet | Hiroshi Ueda |
author_sort | Hiroshi Ueda |
collection | DOAJ |
description | Nuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell death mode switch in serum-starving or ischemic/reperfusion models in vitro and in vivo. Underlying receptor mechanisms include Toll-like receptor 4 (TLR4) and G<sub>i</sub>-coupled receptor. Recent studies have revealed that the mode of the fatal stress-induced extracellular release of nuclear ProTα from cortical neurons in primary cultures, astrocytes and C6 glioma cells has two steps: ATP loss-induced nuclear release and the Ca<sup>2+</sup>-mediated formation of a multiple protein complex and its extracellular release. Under the serum-starving condition, ProTα is diffused from the nucleus throughout the cell due to the ATP loss-induced impairment of importin α–mediated nuclear transport. Subsequent mechanisms are all Ca<sup>2+</sup>-dependent. They include the formation of a protein complex with ProTα, S100A13, p40 Syt-1 and Annexin A2 (ANXA2); the fusion of the protein complex to the plasma membrane via p40 Syt-1–Stx-1 interaction; and TMEM16F scramblase-mediated ANXA2 flop-out. Subsequently, the protein complex is extracellularly released, leaving ANXA2 on the outer cell surface. The ANXA2 is then flipped in by a force of ATP8A2 activity, and the non-vesicular release of protein complex is repeated. Thus, the ANXA2 flop-out could play key roles in a new type of non-vesicular and non-classical release for DAMPs/alarmins, which is distinct from the modes conducted via gasdermin D or mixed-lineage kinase domain-like pseudokinase pores. |
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language | English |
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spelling | doaj.art-060bb517d834470daf36805af4028c452023-11-18T09:42:51ZengMDPI AGCells2073-44092023-06-011212156910.3390/cells12121569Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-OutHiroshi Ueda0Department and Institute of Pharmacology, National Defense Medical Center, Nei-hu, Taipei 114201, TaiwanNuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell death mode switch in serum-starving or ischemic/reperfusion models in vitro and in vivo. Underlying receptor mechanisms include Toll-like receptor 4 (TLR4) and G<sub>i</sub>-coupled receptor. Recent studies have revealed that the mode of the fatal stress-induced extracellular release of nuclear ProTα from cortical neurons in primary cultures, astrocytes and C6 glioma cells has two steps: ATP loss-induced nuclear release and the Ca<sup>2+</sup>-mediated formation of a multiple protein complex and its extracellular release. Under the serum-starving condition, ProTα is diffused from the nucleus throughout the cell due to the ATP loss-induced impairment of importin α–mediated nuclear transport. Subsequent mechanisms are all Ca<sup>2+</sup>-dependent. They include the formation of a protein complex with ProTα, S100A13, p40 Syt-1 and Annexin A2 (ANXA2); the fusion of the protein complex to the plasma membrane via p40 Syt-1–Stx-1 interaction; and TMEM16F scramblase-mediated ANXA2 flop-out. Subsequently, the protein complex is extracellularly released, leaving ANXA2 on the outer cell surface. The ANXA2 is then flipped in by a force of ATP8A2 activity, and the non-vesicular release of protein complex is repeated. Thus, the ANXA2 flop-out could play key roles in a new type of non-vesicular and non-classical release for DAMPs/alarmins, which is distinct from the modes conducted via gasdermin D or mixed-lineage kinase domain-like pseudokinase pores.https://www.mdpi.com/2073-4409/12/12/1569DAMPsalarminsGSDMDMLKLexosomesSNARE complex |
spellingShingle | Hiroshi Ueda Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out Cells DAMPs alarmins GSDMD MLKL exosomes SNARE complex |
title | Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
title_full | Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
title_fullStr | Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
title_full_unstemmed | Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
title_short | Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
title_sort | non vesicular release of alarmin prothymosin α complex associated with annexin 2 flop out |
topic | DAMPs alarmins GSDMD MLKL exosomes SNARE complex |
url | https://www.mdpi.com/2073-4409/12/12/1569 |
work_keys_str_mv | AT hiroshiueda nonvesicularreleaseofalarminprothymosinacomplexassociatedwithannexin2flopout |