Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3
Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However,...
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MDPI AG
2022-12-01
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| Series: | Cells |
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| author | Yangqiu Bai Jinying Liu Xiaoke Jiang Xiuling Li Bingyong Zhang Xiaoying Luo |
| author_facet | Yangqiu Bai Jinying Liu Xiaoke Jiang Xiuling Li Bingyong Zhang Xiaoying Luo |
| author_sort | Yangqiu Bai |
| collection | DOAJ |
| description | Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about the role of nucleophagy in LSEC defenestration. Herein, we aim to dissect the underlying mechanism of progerin and nucleophagy in LSEC phenotype. We found an abnormal accumulation of progerin and a loss of SIRT1 in the nucleus of intrahepatic cells in human fibrotic liver tissue. In vivo, nuclear progerin abnormally accumulated in defenestrated LSECs, along with a depletion of SIRT1 and Cav-1 during liver fibrogenesis, whereas these effects were reversed by the overexpression of SIRT1 with the adenovirus vector. In vitro, H<sub>2</sub>O<sub>2</sub> induced the excessive accumulation of progeirn, with the depletion of Lamin B1 and Cav-1 to aggravate LSEC defenestration. NAC and mito-TEMPO, classical antioxidants, inhibited NOX2- and NOX4-dependent oxidative stress to improve the depletion of Lamin B1 and Cav-1 and promoted progerin-related nucleophagy, leading to a reverse in H<sub>2</sub>O<sub>2</sub>-induced LSEC defenestration. However, rapamycin aggravated the H<sub>2</sub>O<sub>2</sub>-induced depletion of Lamin B1 and Cav-1 due to excessive autophagy, despite promoting progerin nucleophagic degradation. In addition, overexpressing SIRT1 with the adenovirus vector inhibited oxidative stress to rescue the production of Lamin B1 and Cav-1. Moreover, the SIRT1-mediated deacetylation of nuclear LC3 promoted progerin nucleophagic degradation and subsequently inhibited the degradation of Lamin B1 and Cav-1, as well as improved F-actin remodeling, contributing to maintaining LSEC fenestrae. Hence, our findings indicate a new strategy for reversing LSEC defenestration by promoting progerin clearance via the SIRT1-mediated deacetylation of nuclear LC3. |
| first_indexed | 2024-03-09T17:50:26Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-09T17:50:26Z |
| publishDate | 2022-12-01 |
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| spelling | doaj.art-7d7356cd5552474db0c2cee52ea95d032023-11-24T10:45:59ZengMDPI AGCells2073-44092022-12-011123391810.3390/cells11233918Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3Yangqiu Bai0Jinying Liu1Xiaoke Jiang2Xiuling Li3Bingyong Zhang4Xiaoying Luo5Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaDepartment of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaDepartment of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaDepartment of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaDepartment of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaDepartment of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou 450003, ChinaProgerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about the role of nucleophagy in LSEC defenestration. Herein, we aim to dissect the underlying mechanism of progerin and nucleophagy in LSEC phenotype. We found an abnormal accumulation of progerin and a loss of SIRT1 in the nucleus of intrahepatic cells in human fibrotic liver tissue. In vivo, nuclear progerin abnormally accumulated in defenestrated LSECs, along with a depletion of SIRT1 and Cav-1 during liver fibrogenesis, whereas these effects were reversed by the overexpression of SIRT1 with the adenovirus vector. In vitro, H<sub>2</sub>O<sub>2</sub> induced the excessive accumulation of progeirn, with the depletion of Lamin B1 and Cav-1 to aggravate LSEC defenestration. NAC and mito-TEMPO, classical antioxidants, inhibited NOX2- and NOX4-dependent oxidative stress to improve the depletion of Lamin B1 and Cav-1 and promoted progerin-related nucleophagy, leading to a reverse in H<sub>2</sub>O<sub>2</sub>-induced LSEC defenestration. However, rapamycin aggravated the H<sub>2</sub>O<sub>2</sub>-induced depletion of Lamin B1 and Cav-1 due to excessive autophagy, despite promoting progerin nucleophagic degradation. In addition, overexpressing SIRT1 with the adenovirus vector inhibited oxidative stress to rescue the production of Lamin B1 and Cav-1. Moreover, the SIRT1-mediated deacetylation of nuclear LC3 promoted progerin nucleophagic degradation and subsequently inhibited the degradation of Lamin B1 and Cav-1, as well as improved F-actin remodeling, contributing to maintaining LSEC fenestrae. Hence, our findings indicate a new strategy for reversing LSEC defenestration by promoting progerin clearance via the SIRT1-mediated deacetylation of nuclear LC3.https://www.mdpi.com/2073-4409/11/23/3918liver sinusoidal endothelial celldefenestrationprogerinSirtuin 1LC3 |
| spellingShingle | Yangqiu Bai Jinying Liu Xiaoke Jiang Xiuling Li Bingyong Zhang Xiaoying Luo Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 Cells liver sinusoidal endothelial cell defenestration progerin Sirtuin 1 LC3 |
| title | Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 |
| title_full | Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 |
| title_fullStr | Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 |
| title_full_unstemmed | Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 |
| title_short | Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3 |
| title_sort | nucleophagic degradation of progerin ameliorates defenestration in liver sinusoidal endothelium due to sirt1 mediated deacetylation of nuclear lc3 |
| topic | liver sinusoidal endothelial cell defenestration progerin Sirtuin 1 LC3 |
| url | https://www.mdpi.com/2073-4409/11/23/3918 |
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