Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice PMID: 35177641

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2022 Feb 17;13(1):931. doi: 10.1038/s41467-022-28613-0.

Ting Li ^# ¹ ² , Dingyi Lu ^# ¹ , Chengcheng Yao ^# ¹ , Tingting Li ¹ ² , Hua Dong ¹ , Zhan Li ² ³ , Guang Xu ¹ ⁴ , Jiayi Chen ¹ ² , Hao Zhang ⁵ , Xiaoyu Yi ¹ ² , Haizhen Zhu ¹ , Guangqin Liu ¹ ⁶ , Kaiqing Wen ¹ , Haixin Zhao ¹ ⁷ , Jun Gao ¹ , Yakun Zhang ¹ , Qiuying Han ¹ ² , Teng Li ¹ , Weina Zhang ¹ , Jie Zhao ¹ , Tao Li ¹ ² , Zhaofang Bai ⁴ , Moshi Song ⁵ , Xinhua He ² ³ , Tao Zhou ¹ ² , Qing Xia ⁸ ⁹ , Ailing Li ¹⁰ ¹¹ ¹² , Xin Pan ¹³ ¹⁴ ¹⁵

Affiliations

1. State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
2. Nanhu Laboratory, Jiaxing, Zhejiang Province, China.
3. State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China.
4. Military Institute of Chinese Materia, the Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China.
5. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
6. School of Basic Medical Sciences, Fudan University, Shanghai, China.
7. State Key Laboratory of Experimental Haematology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
8. State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China. [email protected].
9. Nanhu Laboratory, Jiaxing, Zhejiang Province, China. [email protected].
10. State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China. [email protected].
11. Nanhu Laboratory, Jiaxing, Zhejiang Province, China. [email protected].
12. School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
13. State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China. [email protected].
14. Nanhu Laboratory, Jiaxing, Zhejiang Province, China. [email protected].
15. School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
# Contributed equally.

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.