SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia
Abstract SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adapta...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07271-8 |
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| author | Alice Zhao Laura Maple Juwei Jiang Katie N. Myers Callum G. Jones Hannah Gagg Connor McGarrity-Cottrell Ola Rominiyi Spencer J. Collis Greg Wells Marufur Rahman Sarah J. Danson Darren Robinson Carl Smythe Chun Guo |
| author_facet | Alice Zhao Laura Maple Juwei Jiang Katie N. Myers Callum G. Jones Hannah Gagg Connor McGarrity-Cottrell Ola Rominiyi Spencer J. Collis Greg Wells Marufur Rahman Sarah J. Danson Darren Robinson Carl Smythe Chun Guo |
| author_sort | Alice Zhao |
| collection | DOAJ |
| description | Abstract SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress. |
| format | Article |
| id | doaj-art-0162534f7f4e46afa780e89c9a03b231 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0162534f7f4e46afa780e89c9a03b2312024-12-08T12:47:32ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211410.1038/s41419-024-07271-8SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxiaAlice Zhao0Laura Maple1Juwei Jiang2Katie N. Myers3Callum G. Jones4Hannah Gagg5Connor McGarrity-Cottrell6Ola Rominiyi7Spencer J. Collis8Greg Wells9Marufur Rahman10Sarah J. Danson11Darren Robinson12Carl Smythe13Chun Guo14School of Biosciences, University of Sheffield, Firth Court, Western BankSchool of Biosciences, University of Sheffield, Firth Court, Western BankSchool of Biosciences, University of Sheffield, Firth Court, Western BankDivision of Clinical Medicine, University of Sheffield Medical SchoolDivision of Clinical Medicine, University of Sheffield Medical SchoolDivision of Clinical Medicine, University of Sheffield Medical SchoolDivision of Clinical Medicine, University of Sheffield Medical SchoolDivision of Clinical Medicine, University of Sheffield Medical SchoolDivision of Clinical Medicine, University of Sheffield Medical SchoolEx vivo Project Team, Division of Clinical Medicine, University of Sheffield Medical SchoolEx vivo Project Team, Division of Clinical Medicine, University of Sheffield Medical SchoolEx vivo Project Team, Division of Clinical Medicine, University of Sheffield Medical SchoolSchool of Biosciences, University of Sheffield, Firth Court, Western BankSchool of Biosciences, University of Sheffield, Firth Court, Western BankSchool of Biosciences, University of Sheffield, Firth Court, Western BankAbstract SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.https://doi.org/10.1038/s41419-024-07271-8 |
| spellingShingle | Alice Zhao Laura Maple Juwei Jiang Katie N. Myers Callum G. Jones Hannah Gagg Connor McGarrity-Cottrell Ola Rominiyi Spencer J. Collis Greg Wells Marufur Rahman Sarah J. Danson Darren Robinson Carl Smythe Chun Guo SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia Cell Death and Disease |
| title | SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia |
| title_full | SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia |
| title_fullStr | SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia |
| title_full_unstemmed | SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia |
| title_short | SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia |
| title_sort | senp3 fis1 axis promotes mitophagy and cell survival under hypoxia |
| url | https://doi.org/10.1038/s41419-024-07271-8 |
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