CD44 connects autophagy decline and ageing in the vascular endothelium

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 and Shiwei Ma
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Lu Zhang: Henan University of Technology
Peichang Yang: Henan University of Technology
Jingxuan Chen: Henan University of Technology
Zhiqiang Chen: Henan University of Technology
Zhihui Liu: Henan University of Technology
Gaoqing Feng: Henan University of Technology
Fangfang Sha: Henan University of Technology
Zirui Li: Henan University of Technology
Zaoyi Xu: Henan University of Technology
Yating Huang: Henan University of Technology
Xiaotong Shi: Henan University of Technology
Xuebiao Li: Henan University of Technology
Jiatian Cui: Henan University of Technology
Chenyi Zhang: Henan University of Technology
Pei Fan: Henan University of Technology
Liuqing Cui: Henan University of Technology
Yunpeng Shen: Henan University of Technology
Guangzhou Zhou: Henan University of Technology
Hongjuan Jing: Henan University of Technology
Shiwei Ma: Henan University of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41346-y

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