MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i>
Oxidative stress resulting from reactive oxygen species and other toxic metabolites is involved in human diseases, and it plays an important role in aging. In <i>Caenorhabditis elegans</i>, SKN-1 is required for protection against oxidative stress and aging. As p38 mitogen-activated prot...
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MDPI AG
2022-10-01
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| Online Access: | https://www.mdpi.com/2079-7737/11/10/1526 |
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| author | Min Hwang Chandani Shrestha Shinwon Kang Jiyoon Kim |
| author_facet | Min Hwang Chandani Shrestha Shinwon Kang Jiyoon Kim |
| author_sort | Min Hwang |
| collection | DOAJ |
| description | Oxidative stress resulting from reactive oxygen species and other toxic metabolites is involved in human diseases, and it plays an important role in aging. In <i>Caenorhabditis elegans</i>, SKN-1 is required for protection against oxidative stress and aging. As p38 mitogen-activated protein kinase signaling is activated in response to oxidative stress, SKN-1 accumulates in intestinal nuclei and induces phase II detoxification genes. However, NSY-1, a well-known mitogen-activated protein kinase kinase kinase (MAPKKK) of <i>C. elegans</i>, acts as a partial regulator of the SKN-1-induced oxidative stress signaling pathway, suggesting that the regulator for optimal activation of SKN-1 remains unknown. Here, we report a MAPKKK, MEKK-3, as a new regulator required for full activation of SKN-1-mediated resistance against oxidative stress and aging. In RNA-interference-based screening, we found that the simultaneous knockdown of <i>mekk-3</i> and <i>nsy-1</i> significantly decreased the oxidative stress resistance and survival of SKN-1 transgenic worms. MEKK-3 was induced in response to oxidative stress. Mechanistic analysis revealed that double knockdown of <i>mekk-3</i> and <i>nsy-1</i> completely suppressed the nuclear localization of SKN-1. These results were reproduced in mutant worms in which SKN-1 is constitutively localized to intestinal nuclei. In addition, <i>mekk-3</i> and <i>nsy-1</i> were required for optimal induction of SKN-1 target genes such as <i>gcs-1</i> and <i>trx-1</i>. These data indicate that MEKK-3 plays an essential role in the SKN-1-dependent signaling pathway involved in oxidative stress resistance and longevity by cooperating with NSY-1. |
| first_indexed | 2024-03-09T20:40:01Z |
| format | Article |
| id | doaj.art-998271a7c15b46a3a7ef1e7d0616a98d |
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| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T20:40:01Z |
| publishDate | 2022-10-01 |
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| spelling | doaj.art-998271a7c15b46a3a7ef1e7d0616a98d2023-11-23T23:01:02ZengMDPI AGBiology2079-77372022-10-011110152610.3390/biology11101526MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i>Min Hwang0Chandani Shrestha1Shinwon Kang2Jiyoon Kim3Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Physiology, University of Toronto, Toronto, ON M5S, CanadaDepartment of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaOxidative stress resulting from reactive oxygen species and other toxic metabolites is involved in human diseases, and it plays an important role in aging. In <i>Caenorhabditis elegans</i>, SKN-1 is required for protection against oxidative stress and aging. As p38 mitogen-activated protein kinase signaling is activated in response to oxidative stress, SKN-1 accumulates in intestinal nuclei and induces phase II detoxification genes. However, NSY-1, a well-known mitogen-activated protein kinase kinase kinase (MAPKKK) of <i>C. elegans</i>, acts as a partial regulator of the SKN-1-induced oxidative stress signaling pathway, suggesting that the regulator for optimal activation of SKN-1 remains unknown. Here, we report a MAPKKK, MEKK-3, as a new regulator required for full activation of SKN-1-mediated resistance against oxidative stress and aging. In RNA-interference-based screening, we found that the simultaneous knockdown of <i>mekk-3</i> and <i>nsy-1</i> significantly decreased the oxidative stress resistance and survival of SKN-1 transgenic worms. MEKK-3 was induced in response to oxidative stress. Mechanistic analysis revealed that double knockdown of <i>mekk-3</i> and <i>nsy-1</i> completely suppressed the nuclear localization of SKN-1. These results were reproduced in mutant worms in which SKN-1 is constitutively localized to intestinal nuclei. In addition, <i>mekk-3</i> and <i>nsy-1</i> were required for optimal induction of SKN-1 target genes such as <i>gcs-1</i> and <i>trx-1</i>. These data indicate that MEKK-3 plays an essential role in the SKN-1-dependent signaling pathway involved in oxidative stress resistance and longevity by cooperating with NSY-1.https://www.mdpi.com/2079-7737/11/10/1526longevityoxidative stress<i>Caenorhabditis elegans</i>MEKK-3NSY-1SKN-1 |
| spellingShingle | Min Hwang Chandani Shrestha Shinwon Kang Jiyoon Kim MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> Biology longevity oxidative stress <i>Caenorhabditis elegans</i> MEKK-3 NSY-1 SKN-1 |
| title | MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> |
| title_full | MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> |
| title_fullStr | MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> |
| title_full_unstemmed | MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> |
| title_short | MEKK-3 Acts Cooperatively with NSY-1 in SKN-1-Dependent Manner against Oxidative Stress and Aging in <i>Caenorhabditis elegans</i> |
| title_sort | mekk 3 acts cooperatively with nsy 1 in skn 1 dependent manner against oxidative stress and aging in i caenorhabditis elegans i |
| topic | longevity oxidative stress <i>Caenorhabditis elegans</i> MEKK-3 NSY-1 SKN-1 |
| url | https://www.mdpi.com/2079-7737/11/10/1526 |
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