Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice

Ting Li, Dingyi Lu, Chengcheng Yao, Tingting Li, Hua Dong, Zhan Li, Guang Xu, Jiayi Chen, Hao Zhang, Xiaoyu Yi, Haizhen Zhu, Guangqin Liu, Kaiqing Wen, Haixin Zhao, Jun Gao, Yakun Zhang, Qiuying Han, Teng Li, Weina Zhang, Jie Zhao, Tao Li, Zhaofang Bai, Moshi Song, Xinhua He, Tao Zhou, Qing Xia (), Ailing Li () and Xin Pan ()
Additional contact information
Ting Li: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Dingyi Lu: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Chengcheng Yao: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Tingting Li: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Hua Dong: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Zhan Li: Nanhu Laboratory
Guang Xu: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Jiayi Chen: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Hao Zhang: Institute of Zoology, Chinese Academy of Sciences
Xiaoyu Yi: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Haizhen Zhu: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Guangqin Liu: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Kaiqing Wen: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Haixin Zhao: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Jun Gao: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Yakun Zhang: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Qiuying Han: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Teng Li: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Weina Zhang: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Jie Zhao: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Tao Li: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Zhaofang Bai: Military Institute of Chinese Materia, the Fifth Medical Centre of Chinese PLA General Hospital
Moshi Song: Institute of Zoology, Chinese Academy of Sciences
Xinhua He: Nanhu Laboratory
Tao Zhou: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Qing Xia: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Ailing Li: Institute of Basic Medical Sciences, National Center of Biomedical Analysis
Xin Pan: Institute of Basic Medical Sciences, National Center of Biomedical Analysis

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/− mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/− mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.

Date: 2022
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DOI: 10.1038/s41467-022-28613-0

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