A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response
The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Cae...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71634 |
| _version_ | 1811252339064963072 |
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| author | James P Held Gaomin Feng Benjamin R Saunders Claudia V Pereira Kristopher Burkewitz Maulik R Patel |
| author_facet | James P Held Gaomin Feng Benjamin R Saunders Claudia V Pereira Kristopher Burkewitz Maulik R Patel |
| author_sort | James P Held |
| collection | DOAJ |
| description | The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing toward its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt. |
| first_indexed | 2024-04-12T16:33:13Z |
| format | Article |
| id | doaj.art-c81b9865a2cf48a6b5e913ca67b984b5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:33:13Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c81b9865a2cf48a6b5e913ca67b984b52022-12-22T03:25:05ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.71634A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein responseJames P Held0https://orcid.org/0000-0003-4322-2108Gaomin Feng1Benjamin R Saunders2Claudia V Pereira3Kristopher Burkewitz4Maulik R Patel5https://orcid.org/0000-0003-3749-0122Department of Biological Sciences, Vanderbilt University, Nashville, United StatesDepartment of Cell and Developmental Biology, Vanderbilt University, Nashville, United StatesDepartment of Biological Sciences, Vanderbilt University, Nashville, United StatesDepartment of Biological Sciences, Vanderbilt University, Nashville, United StatesDepartment of Cell and Developmental Biology, Vanderbilt University, Nashville, United StatesDepartment of Biological Sciences, Vanderbilt University, Nashville, United States; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States; Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, United StatesThe mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing toward its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.https://elifesciences.org/articles/71634mitochondriamitochondrial unfolded protein responseELAC2/HOE-1tRNAs |
| spellingShingle | James P Held Gaomin Feng Benjamin R Saunders Claudia V Pereira Kristopher Burkewitz Maulik R Patel A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response eLife mitochondria mitochondrial unfolded protein response ELAC2/HOE-1 tRNAs |
| title | A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| title_full | A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| title_fullStr | A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| title_full_unstemmed | A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| title_short | A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| title_sort | trna processing enzyme is a key regulator of the mitochondrial unfolded protein response |
| topic | mitochondria mitochondrial unfolded protein response ELAC2/HOE-1 tRNAs |
| url | https://elifesciences.org/articles/71634 |
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