OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes
Olfactory receptors (ORs) are the largest protein superfamily in mammals. Certain ORs are ectopically expressed in extranasal tissues and regulate cell type-specific signal transduction pathways. OR2AT4 is ectopically expressed in skin cells and promotes wound healing and hair growth. As the capacit...
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MDPI AG
2022-11-01
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| Series: | Antioxidants |
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| author | Ji-Sun Kim Ha Lim Lee Ji Hyun Jeong Ye Eun Yoon In-Ryeong Lee Ji Min Kim Chunyan Wu Sung-Joon Lee |
| author_facet | Ji-Sun Kim Ha Lim Lee Ji Hyun Jeong Ye Eun Yoon In-Ryeong Lee Ji Min Kim Chunyan Wu Sung-Joon Lee |
| author_sort | Ji-Sun Kim |
| collection | DOAJ |
| description | Olfactory receptors (ORs) are the largest protein superfamily in mammals. Certain ORs are ectopically expressed in extranasal tissues and regulate cell type-specific signal transduction pathways. OR2AT4 is ectopically expressed in skin cells and promotes wound healing and hair growth. As the capacities of wound healing and hair growth decline with aging, we investigated the role of OR2AT4 in the aging and senescence of human keratinocytes. OR2AT4 was functionally expressed in human keratinocytes (HaCaT) and exhibited co-expression with G-protein-coupled receptor signaling components, G<sub>olfα</sub> and adenylate cyclase 3. The OR2AT4 ligand sandalore modulates the intracellular calcium, inositol phosphate, and cyclic adenosine monophosphate (cAMP) levels. The increased calcium level induced by sandalore was attenuated in cells with <i>OR2AT4</i> knockdown. OR2AT4 activation by sandalore inhibited the senescent cell phenotypes and restored cell proliferation and Ki-67 expression. Sandalore also inhibited the expression of senescence-associated β-galactosidase and increased p21 expression in senescent HaCaT cells in response to hydrogen peroxide. Additionally, sandalore activated the CaMKKβ/AMPK/mTORC1/autophagy signaling axis and promoted autophagy. <i>OR2AT4</i> knockdown attenuated the increased in the intracellular calcium level, cell proliferation, and AMPK phosphorylation induced by sandalore. These findings demonstrate that the effects of sandalore are mediated by OR2AT4 activation. Our findings suggest that OR2AT4 may be a novel therapeutic target for anti-aging and anti-senescence in human keratinocytes. |
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| last_indexed | 2024-03-09T19:18:47Z |
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| series | Antioxidants |
| spelling | doaj.art-17e8b12b3a2e4675863df0aa74d480572023-11-24T03:30:32ZengMDPI AGAntioxidants2076-39212022-11-011111218010.3390/antiox11112180OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human KeratinocytesJi-Sun Kim0Ha Lim Lee1Ji Hyun Jeong2Ye Eun Yoon3In-Ryeong Lee4Ji Min Kim5Chunyan Wu6Sung-Joon Lee7Department of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Graduate School of Life Science & Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, KoreaOlfactory receptors (ORs) are the largest protein superfamily in mammals. Certain ORs are ectopically expressed in extranasal tissues and regulate cell type-specific signal transduction pathways. OR2AT4 is ectopically expressed in skin cells and promotes wound healing and hair growth. As the capacities of wound healing and hair growth decline with aging, we investigated the role of OR2AT4 in the aging and senescence of human keratinocytes. OR2AT4 was functionally expressed in human keratinocytes (HaCaT) and exhibited co-expression with G-protein-coupled receptor signaling components, G<sub>olfα</sub> and adenylate cyclase 3. The OR2AT4 ligand sandalore modulates the intracellular calcium, inositol phosphate, and cyclic adenosine monophosphate (cAMP) levels. The increased calcium level induced by sandalore was attenuated in cells with <i>OR2AT4</i> knockdown. OR2AT4 activation by sandalore inhibited the senescent cell phenotypes and restored cell proliferation and Ki-67 expression. Sandalore also inhibited the expression of senescence-associated β-galactosidase and increased p21 expression in senescent HaCaT cells in response to hydrogen peroxide. Additionally, sandalore activated the CaMKKβ/AMPK/mTORC1/autophagy signaling axis and promoted autophagy. <i>OR2AT4</i> knockdown attenuated the increased in the intracellular calcium level, cell proliferation, and AMPK phosphorylation induced by sandalore. These findings demonstrate that the effects of sandalore are mediated by OR2AT4 activation. Our findings suggest that OR2AT4 may be a novel therapeutic target for anti-aging and anti-senescence in human keratinocytes.https://www.mdpi.com/2076-3921/11/11/2180olfactory receptorOR2AT4sandaloresenescencehuman keratinocytesCaMKKβ/AMPK/mTORC1/autophagy signaling |
| spellingShingle | Ji-Sun Kim Ha Lim Lee Ji Hyun Jeong Ye Eun Yoon In-Ryeong Lee Ji Min Kim Chunyan Wu Sung-Joon Lee OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes Antioxidants olfactory receptor OR2AT4 sandalore senescence human keratinocytes CaMKKβ/AMPK/mTORC1/autophagy signaling |
| title | OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes |
| title_full | OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes |
| title_fullStr | OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes |
| title_full_unstemmed | OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes |
| title_short | OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes |
| title_sort | or2at4 an ectopic olfactory receptor suppresses oxidative stress induced senescence in human keratinocytes |
| topic | olfactory receptor OR2AT4 sandalore senescence human keratinocytes CaMKKβ/AMPK/mTORC1/autophagy signaling |
| url | https://www.mdpi.com/2076-3921/11/11/2180 |
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