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- Title
CD44 connects autophagy decline and ageing in the vascular endothelium.
- Authors
Zhang, Lu; Yang, Peichang; Chen, Jingxuan; Chen, Zhiqiang; Liu, Zhihui; Feng, Gaoqing; Sha, Fangfang; Li, Zirui; Xu, Zaoyi; Huang, Yating; Shi, Xiaotong; Li, Xuebiao; Cui, Jiatian; Zhang, Chenyi; Fan, Pei; Cui, Liuqing; Shen, Yunpeng; Zhou, Guangzhou; Jing, Hongjuan; Ma, Shiwei
- 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. Mechanisms underlying the connection between autophagy decline and vascular endothelial cell (VEC) ageing remain unclear. Here, the authors identify a key role for CD44 in controlling autophagy and ageing in VECs, and this function is conserved in nematodes.
- Subjects
VASCULAR endothelium; CD44 antigen; ENDOTHELIUM; AUTOPHAGY; VASCULAR endothelial cells; PREMATURE aging (Medicine)
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41346-y