State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
Nanhu Laboratory, Jiaxing, Zhejiang Province, China.
Nat Commun. 2022 Feb 17;13(1):931. doi: 10.1038/s41467-022-28613-0.
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.
Koolen-de Vries 综合征（KdVS）是一种由 KAT8 调节 NSL 复合物亚单位 1（KANSL1）单倍体不足引起的罕见疾病，其特征为智力障碍、心力衰竭、张力减退和先天性畸形。迄今为止，尚未发现针对 KdVS 的有效治疗方法，主要是因为其发病机制尚不清楚。我们使用 siRNA 筛选发现 KANSL1 是自噬所必需的基因。机制研究表明，KANSL1 通过转录调节自噬体基因 STX17 来调节自噬体 - 溶酶体融合以进行货物降解。Kansl1 小鼠在受损线粒体的自噬清除和活性氧积累方面存在缺陷，从而导致神经元和心脏功能缺陷。此外，我们发现，美国食品和药物管理局批准的药物 13-顺式视黄酸可通过促进自噬体 - 溶酶体融合来逆转 Kansl1 小鼠的这些噬线粒体缺陷和神经行为异常。因此，这些发现表明 KANSL1 在自噬中的关键作用，并为 KdVS 提供了一种潜在可行的治疗策略。
