CD44 connects autophagy decline and ageing in the vascular endothelium
Abstract The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in con...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41346-y |
| _version_ | 1797557872409706496 |
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| author | Lu Zhang Peichang Yang Jingxuan Chen Zhiqiang Chen Zhihui Liu Gaoqing Feng Fangfang Sha Zirui Li Zaoyi Xu Yating Huang Xiaotong Shi Xuebiao Li Jiatian Cui Chenyi Zhang Pei Fan Liuqing Cui Yunpeng Shen Guangzhou Zhou Hongjuan Jing Shiwei Ma |
| author_facet | Lu Zhang Peichang Yang Jingxuan Chen Zhiqiang Chen Zhihui Liu Gaoqing Feng Fangfang Sha Zirui Li Zaoyi Xu Yating Huang Xiaotong Shi Xuebiao Li Jiatian Cui Chenyi Zhang Pei Fan Liuqing Cui Yunpeng Shen Guangzhou Zhou Hongjuan Jing Shiwei Ma |
| author_sort | Lu Zhang |
| collection | DOAJ |
| description | Abstract The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing. |
| first_indexed | 2024-03-10T17:23:24Z |
| format | Article |
| id | doaj.art-6b774202582b4de98264ab2c39d185b6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:23:24Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6b774202582b4de98264ab2c39d185b62023-11-20T10:16:30ZengNature PortfolioNature Communications2041-17232023-09-0114111810.1038/s41467-023-41346-yCD44 connects autophagy decline and ageing in the vascular endotheliumLu Zhang0Peichang Yang1Jingxuan Chen2Zhiqiang Chen3Zhihui Liu4Gaoqing Feng5Fangfang Sha6Zirui Li7Zaoyi Xu8Yating Huang9Xiaotong Shi10Xuebiao Li11Jiatian Cui12Chenyi Zhang13Pei Fan14Liuqing Cui15Yunpeng Shen16Guangzhou Zhou17Hongjuan Jing18Shiwei Ma19College of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyCollege of Bioengineering, Henan University of TechnologyAbstract The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.https://doi.org/10.1038/s41467-023-41346-y |
| spellingShingle | Lu Zhang Peichang Yang Jingxuan Chen Zhiqiang Chen Zhihui Liu Gaoqing Feng Fangfang Sha Zirui Li Zaoyi Xu Yating Huang Xiaotong Shi Xuebiao Li Jiatian Cui Chenyi Zhang Pei Fan Liuqing Cui Yunpeng Shen Guangzhou Zhou Hongjuan Jing Shiwei Ma CD44 connects autophagy decline and ageing in the vascular endothelium Nature Communications |
| title | CD44 connects autophagy decline and ageing in the vascular endothelium |
| title_full | CD44 connects autophagy decline and ageing in the vascular endothelium |
| title_fullStr | CD44 connects autophagy decline and ageing in the vascular endothelium |
| title_full_unstemmed | CD44 connects autophagy decline and ageing in the vascular endothelium |
| title_short | CD44 connects autophagy decline and ageing in the vascular endothelium |
| title_sort | cd44 connects autophagy decline and ageing in the vascular endothelium |
| url | https://doi.org/10.1038/s41467-023-41346-y |
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