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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296757/ https://www.ncbi.nlm.nih.gov/pubmed/37371039 http://dx.doi.org/10.3390/cells12121569 |
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author | Ueda, Hiroshi |
author_facet | Ueda, Hiroshi |
author_sort | Ueda, Hiroshi |
collection | PubMed |
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(i)-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(2+)-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(2+)-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. |
format | Online Article Text |
id | pubmed-10296757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102967572023-06-28 Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out Ueda, Hiroshi Cells Review 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(i)-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(2+)-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(2+)-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. MDPI 2023-06-06 /pmc/articles/PMC10296757/ /pubmed/37371039 http://dx.doi.org/10.3390/cells12121569 Text en © 2023 by the author. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Ueda, Hiroshi Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out |
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 | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296757/ https://www.ncbi.nlm.nih.gov/pubmed/37371039 http://dx.doi.org/10.3390/cells12121569 |
work_keys_str_mv | AT uedahiroshi nonvesicularreleaseofalarminprothymosinacomplexassociatedwithannexin2flopout |