Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity
Unfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it w...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/44425 |
| _version_ | 1818026962782781440 |
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| author | Nicolas J Lehrbach Gary Ruvkun |
| author_facet | Nicolas J Lehrbach Gary Ruvkun |
| author_sort | Nicolas J Lehrbach |
| collection | DOAJ |
| description | Unfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it was not established whether SKN-1A/Nrf1 adjusts proteasome capacity in response to other proteotoxic insults. Here, we reveal that misfolded endogenous proteins and the human amyloid beta peptide trigger activation of proteasome subunit expression by SKN-1A/Nrf1. SKN-1A activation is protective against age-dependent defects caused by accumulation of misfolded and aggregation-prone proteins. In a C. elegans Alzheimer’s disease model, SKN-1A/Nrf1 slows accumulation of the amyloid beta peptide and delays adult-onset cellular dysfunction. Our results indicate that SKN-1A surveys cellular protein folding and adjusts proteasome capacity to meet the demands of protein quality control pathways, revealing a new arm of the cytosolic UPR. This regulatory axis is critical for healthy aging and may be a target for therapeutic modulation of human aging and age-related disease. |
| first_indexed | 2024-12-10T04:40:20Z |
| format | Article |
| id | doaj.art-f5974a52640c49b1a5150c7615c67079 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:40:20Z |
| publishDate | 2019-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f5974a52640c49b1a5150c7615c670792022-12-22T02:01:55ZengeLife Sciences Publications LtdeLife2050-084X2019-04-01810.7554/eLife.44425Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevityNicolas J Lehrbach0https://orcid.org/0000-0001-7342-4136Gary Ruvkun1https://orcid.org/0000-0002-7473-8484Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Genetics, Harvard Medical School, Boston, United StatesDepartment of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Genetics, Harvard Medical School, Boston, United StatesUnfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it was not established whether SKN-1A/Nrf1 adjusts proteasome capacity in response to other proteotoxic insults. Here, we reveal that misfolded endogenous proteins and the human amyloid beta peptide trigger activation of proteasome subunit expression by SKN-1A/Nrf1. SKN-1A activation is protective against age-dependent defects caused by accumulation of misfolded and aggregation-prone proteins. In a C. elegans Alzheimer’s disease model, SKN-1A/Nrf1 slows accumulation of the amyloid beta peptide and delays adult-onset cellular dysfunction. Our results indicate that SKN-1A surveys cellular protein folding and adjusts proteasome capacity to meet the demands of protein quality control pathways, revealing a new arm of the cytosolic UPR. This regulatory axis is critical for healthy aging and may be a target for therapeutic modulation of human aging and age-related disease.https://elifesciences.org/articles/44425proteasomeUPRagingSKN-1NFE2L1protein quality control |
| spellingShingle | Nicolas J Lehrbach Gary Ruvkun Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity eLife proteasome UPR aging SKN-1 NFE2L1 protein quality control |
| title | Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| title_full | Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| title_fullStr | Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| title_full_unstemmed | Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| title_short | Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| title_sort | endoplasmic reticulum associated skn 1a nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity |
| topic | proteasome UPR aging SKN-1 NFE2L1 protein quality control |
| url | https://elifesciences.org/articles/44425 |
| work_keys_str_mv | AT nicolasjlehrbach endoplasmicreticulumassociatedskn1anrf1mediatesacytoplasmicunfoldedproteinresponseandpromoteslongevity AT garyruvkun endoplasmicreticulumassociatedskn1anrf1mediatesacytoplasmicunfoldedproteinresponseandpromoteslongevity |