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Cells
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Immune- and Neurobiology of Prothymosin Alpha
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Immune- and Neurobiology of Prothymosin Alpha

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 8724

Special Issue Editors

Prof. Dr. Hiroshi Ueda

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Guest Editor
Emer. Prof. of Nagasaki Univ. Laboratory for the Study of Pain Research Institute for Production Development 15 Shimogamo Morimoto-cho, Sakyo-ku, Kyoto 606-0805, Japan
Interests: prothymosin α; stroke; DAMPs/alarmins; chronic pain; fibromyalgia; opioid receptor
Special Issues, Collections and Topics in MDPI journals
Dr. Sebok Kumar Halder

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Guest Editor
San Diego Biomedical Research Institute, San Diego, CA, USA
Interests: neurological disorders; hypoxia; neurovascular protection; ischemia; DAMPs; angiogenesis

Special Issue Information

Dear Colleagues,

Prothymosin alpha (ProTα), an immunoreactive polypeptide, was isolated from rat thymus in 1984. Initially, ProTα was thought to be a precursor of thymosin α1, but subsequent studies that suggested ProTα may have intrinsic biological actions different from those of thymosin α1. Since then, two important findings have been reported. Jiang et al. (2003) reported that ProTα disrupts apoptosome functions by binding to ApaF1. Interestingly, a later study (2007) revealed that ProTα converts starvation-induced neuronal necrotic cell death to an apoptotic one. A series of studies by the latter group have further revealed that ProTαis is released from neurons due to several intense stresses in a non-classical and non-vesicular way. These reports suggest that ProTα may have distinct cell type-specific actions in cell death mechanisms. Further studies have recently suggested that ProTα exhibits neurogenerative actions, possibly through a putative cell surface receptor as a DAMPs/alarmins member. Here, we intend to invite ProTα-related studies and to sort out and understand the immunobiology and neurobiology of ProTα.

Prof. Dr. Hiroshi Ueda
Dr. Sebok Kumar Halder
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DAMPs/alarmins
  • non-classical and non-vesicular release
  • cell death mode switch
  • neurogenesis
  • ApaF1
  • apoptosome
  • autophagy

Published Papers (3 papers)

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Review

14 pages, 3133 KiB  
Review
Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out
by Hiroshi Ueda
Cells 2023, 12(12), 1569; https://doi.org/10.3390/cells12121569 - 06 Jun 2023
Cited by 1 | Viewed by 1339
Abstract
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) [...] Read more.
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 Gi-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 Ca2+-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 Ca2+-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. Full article
(This article belongs to the Special Issue Immune- and Neurobiology of Prothymosin Alpha)
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16 pages, 1795 KiB  
Review
Prothymosin α Plays Role as a Brain Guardian through Ecto-F1 ATPase-P2Y12 Complex and TLR4/MD2
by Hiroshi Ueda
Cells 2023, 12(3), 496; https://doi.org/10.3390/cells12030496 - 02 Feb 2023
Cited by 4 | Viewed by 1858
Abstract
Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by [...] Read more.
Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by a variety of neurotrophic factors (NTFs). This type of NTF-assisted survival action of ProTα is reproduced in cerebral and retinal ischemia–reperfusion models. Further studies that used a retinal ischemia–reperfusion model revealed that ProTα protects retinal cells via ecto-F1 ATPase coupled with the Gi-coupled P2Y12 receptor and Toll-like receptor 4 (TLR4)/MD2 coupled with a Toll–IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). In cerebral ischemia–reperfusion models, ProTα has additional survival mechanisms via an inhibition of matrix metalloproteases in microglia and vascular endothelial cells. Heterozygous or conditional ProTα knockout mice show phenotypes of anxiety, memory learning impairment, and a loss of neurogenesis. There are many reports that ProTα has multiple intracellular functions for cell survival and proliferation through a variety of protein–protein interactions. Overall, it is suggested that ProTα plays a key role as a brain guardian against ischemia stress through a cell-death-mode switch assisted by NTFs and a role of neurogenesis. Full article
(This article belongs to the Special Issue Immune- and Neurobiology of Prothymosin Alpha)
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Figure 1

21 pages, 1316 KiB  
Review
Immunogenic Cell Death, DAMPs and Prothymosin α as a Putative Anticancer Immune Response Biomarker
by Anastasios I. Birmpilis, Antonios Paschalis, Apostolis Mourkakis, Panayiota Christodoulou, Ioannis V. Kostopoulos, Elina Antimissari, Georgia Terzoudi, Alexandros G. Georgakilas, Christina Armpilia, Panagiotis Papageorgis, Efstathios Kastritis, Evangelos Terpos, Meletios A. Dimopoulos, Hubert Kalbacher, Evangelia Livaniou, Maria-Ioanna Christodoulou and Ourania E. Tsitsilonis
Cells 2022, 11(9), 1415; https://doi.org/10.3390/cells11091415 - 22 Apr 2022
Cited by 34 | Viewed by 4915
Abstract
The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A [...] Read more.
The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100–109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100–109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100–109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation. Full article
(This article belongs to the Special Issue Immune- and Neurobiology of Prothymosin Alpha)
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