Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging

被引：13

作者：

Guo R. ^{[1
,2
]}

Liu J. ^{[2
]}

Min X. ^{[2
,3
]}

Zeng W. ^{[2
,3
]}

Shan B. ^{[2
]}

Zhang M. ^{[2
]}

He Z. ^{[2
]}

Zhang Y. ^{[2
,4
]}

He K. ^{[2
]}

Yuan J. ^{[2
]}

Xu D. ^{[2
,4
]}

机构：

[1] College of Life Sciences, Nankai University, Tianjin

[2] Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai

[3] University of Chinese Academy of Sciences, Beijing

[4] Shanghai Key Laboratory of Aging Studies, Shanghai

来源：

Nature Structural & Molecular Biology | 2024年 / 31卷 / 2期

基金：

中国国家自然科学基金;

关键词：

D O I：

10.1038/s41594-023-01163-9

中图分类号：

学科分类号：

摘要：

Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer’s disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.; Autophagy is essential for cellular homeostasis which decreases with age. Here, the authors identify aging-induced reduction of DHHC5-mediated beclin 1 palmitoylation as an underlying mechanism by which aging induces autophagy decline in the brain. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024..

引用

页码：232 / 245

页数：13

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