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Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that acts as a transcriptional repressor in hypoxia and as a pro-apoptotic protein involved in neuronal cell death. Npas4 (NXF or LE-PAS) is a transcriptional factor that protects nerve cells from endogenous and foreign neurotoxins. Here...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531447/ https://www.ncbi.nlm.nih.gov/pubmed/34675183 http://dx.doi.org/10.1038/s41420-021-00690-y |
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author | Kasai, Shuya Li, Xianyu Torii, Satoru Yasumoto, Ken-ichi Sogawa, Kazuhiro |
author_facet | Kasai, Shuya Li, Xianyu Torii, Satoru Yasumoto, Ken-ichi Sogawa, Kazuhiro |
author_sort | Kasai, Shuya |
collection | PubMed |
description | Inhibitory PAS domain protein (IPAS) is a bifunctional protein that acts as a transcriptional repressor in hypoxia and as a pro-apoptotic protein involved in neuronal cell death. Npas4 (NXF or LE-PAS) is a transcriptional factor that protects nerve cells from endogenous and foreign neurotoxins. Here we show that IPAS and Npas4 antagonize each other through their direct interaction. Coimmunoprecipitation experiments revealed that multiple binding sites on each protein were involved in the interaction. CoCl(2) treatment of PC12 cells that induces IPAS repressed the transactivation activity of Npas4, and IPAS siRNA treatment reduced the CoCl(2)-induced repression. CoCl(2)-induced apoptosis was suppressed by the addition of KCl that induces Npas4. The protective effect of KCl was attenuated by siRNA-mediated gene silencing of Npas4. Npas4 and IPAS proteins were induced and localized in the cytoplasm of the dopaminergic neurons in the substantia nigra pars compacta after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Npas4(−/−) mice exhibited greater sensitivity to MPTP in nigral dopaminergic neurons. Together, these results strongly suggest that neuroprotective activity of Npas4 was, at least partly, exerted by inhibiting the pro-apoptotic activity of IPAS through direct interaction. |
format | Online Article Text |
id | pubmed-8531447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85314472021-11-04 Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death Kasai, Shuya Li, Xianyu Torii, Satoru Yasumoto, Ken-ichi Sogawa, Kazuhiro Cell Death Discov Article Inhibitory PAS domain protein (IPAS) is a bifunctional protein that acts as a transcriptional repressor in hypoxia and as a pro-apoptotic protein involved in neuronal cell death. Npas4 (NXF or LE-PAS) is a transcriptional factor that protects nerve cells from endogenous and foreign neurotoxins. Here we show that IPAS and Npas4 antagonize each other through their direct interaction. Coimmunoprecipitation experiments revealed that multiple binding sites on each protein were involved in the interaction. CoCl(2) treatment of PC12 cells that induces IPAS repressed the transactivation activity of Npas4, and IPAS siRNA treatment reduced the CoCl(2)-induced repression. CoCl(2)-induced apoptosis was suppressed by the addition of KCl that induces Npas4. The protective effect of KCl was attenuated by siRNA-mediated gene silencing of Npas4. Npas4 and IPAS proteins were induced and localized in the cytoplasm of the dopaminergic neurons in the substantia nigra pars compacta after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Npas4(−/−) mice exhibited greater sensitivity to MPTP in nigral dopaminergic neurons. Together, these results strongly suggest that neuroprotective activity of Npas4 was, at least partly, exerted by inhibiting the pro-apoptotic activity of IPAS through direct interaction. Nature Publishing Group UK 2021-10-21 /pmc/articles/PMC8531447/ /pubmed/34675183 http://dx.doi.org/10.1038/s41420-021-00690-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kasai, Shuya Li, Xianyu Torii, Satoru Yasumoto, Ken-ichi Sogawa, Kazuhiro Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title | Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title_full | Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title_fullStr | Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title_full_unstemmed | Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title_short | Direct protein–protein interaction between Npas4 and IPAS mutually inhibits their critical roles in neuronal cell survival and death |
title_sort | direct protein–protein interaction between npas4 and ipas mutually inhibits their critical roles in neuronal cell survival and death |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531447/ https://www.ncbi.nlm.nih.gov/pubmed/34675183 http://dx.doi.org/10.1038/s41420-021-00690-y |
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