Abrar F, Davies M C, Alshehabi Y, Kumar A, Dang A, Nguyen Y T N, Collins J, Caron N S, Choudhary J S, Sanders S S, Collins M O, Hayden M R, Martin D D O
Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
Molecular and Cell Biology Cluster, School of Biosciences, University of Sheffield, Sheffield, UK.
FASEB J. 2025 May 15;39(9):e70549. doi: 10.1096/fj.202401781R.
Disruption of autophagy has emerged as a common feature in many neurodegenerative diseases. Autophagy is a membrane-dependent pathway that requires many key regulators to quickly localize on and off membranes during induction, promoting membrane fusion. Previously, our bioinformatic approaches have shown that autophagy and Huntington disease (HD) are enriched in palmitoylated proteins. Palmitoylation involves the reversible addition of long-chain fatty acids to promote membrane binding. Herein, we show that inhibition of palmitoylation regulates the abundance of several key regulators of autophagy and leads to a partial block of autophagic flux. We confirm that the autophagy receptor SQSTM1/p62 (sequestosome 1) is palmitoylated and directed to the lysosome. Importantly, we report that SQSTM1 palmitoylation is significantly reduced in HD patient and mouse model brains. This finding reveals a novel mechanism contributing to the generation of empty autophagosomes previously seen in HD models and patient-derived cells.
自噬功能紊乱已成为许多神经退行性疾病的一个共同特征。自噬是一种依赖膜的途径，在诱导过程中需要许多关键调节因子快速定位在膜上和离开膜，促进膜融合。此前，我们的生物信息学方法表明，自噬和亨廷顿舞蹈症（HD）在棕榈酰化蛋白中富集。棕榈酰化涉及长链脂肪酸的可逆添加以促进膜结合。在此，我们表明抑制棕榈酰化可调节几种自噬关键调节因子的丰度，并导致自噬流部分受阻。我们证实自噬受体SQSTM1/p62（聚集体蛋白1）被棕榈酰化并靶向溶酶体。重要的是，我们报告在HD患者和小鼠模型脑内，SQSTM1的棕榈酰化显著降低。这一发现揭示了一种新机制，有助于解释先前在HD模型和患者来源细胞中出现的空自噬体的产生。
