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

作者：Ting Li, Dingyi Lu, Chengcheng Yao, Tingting Li, Hua Dong, Zhan Li, Guang Xu, Jiayi Chen, Hao Zhang, Xiaoyu Yi, Hai-Zhen 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, Xin Pan · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-28613-0 · 被引用次数：51 · 研究领域：RNA modifications and cancer、RNA Interference and Gene Delivery、Autophagy in Disease and Therapy

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.