Alshehabi Y, Abrar F, Martin D D O
Department of Biology, University of Waterloo, Waterloo, ON, Canada.
Autophagy Rep. 2025 Aug 25;4(1):2547975. doi: 10.1080/27694127.2025.2547975. eCollection 2025.
Protein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various neurodegenerative diseases, including Huntington disease (HD). We identified S-acylation, a reversible lipid modification of proteins, as an important regulator in protein trafficking and autophagy. SQSTM1 (sequestosome 1/p62) is an essential selective autophagy receptor for the sequestration of ubiquitinated cargoes within autophagosomes and subsequent delivery into lysosomes for degradation. Recently, we reported that S-acylation of SQSTM1 at the di-cysteine motif C289,290 directs SQSTM1 to lysosomes. We further showed that SQSTM1 S-acylation is significantly reduced in brains from both HD patients and mouse HD model, which may result in the cargo sequestration defect within autophagosomes in HD. Treatment with palmostatin B, a deacylation inhibitor, significantly increases SQSTM1 localization to lysosomes. Our work highlights SQSTM1 S-acylation as a novel potential therapeutic strategy in HD. As a crucial autophagy component, our work suggests S-acylation of SQSTM1 may have a broader role in neurodegeneration.
蛋白质错误定位和聚集是神经退行性变的标志性特征。随着蛋白质错误定位，蛋白质稳态缺陷和蛋白质聚集通常会随之而来。自噬是清除蛋白质聚集体以维持神经元健康的关键途径，但在包括亨廷顿病（HD）在内的各种神经退行性疾病中会受损。我们发现蛋白质的可逆脂质修饰——S-酰化，是蛋白质运输和自噬的重要调节因子。SQSTM1（sequestosome 1/p62）是一种重要的选择性自噬受体，用于在自噬小体内隔离泛素化货物，并随后将其递送至溶酶体进行降解。最近，我们报道了SQSTM1在二硫基序C289,290处的S-酰化将SQSTM1导向溶酶体。我们进一步表明，HD患者和小鼠HD模型大脑中的SQSTM1 S-酰化显著降低，这可能导致HD中自噬小体内的货物隔离缺陷。用去酰化抑制剂棕榈抑素B治疗可显著增加SQSTM1在溶酶体中的定位。我们的工作突出了SQSTM1 S-酰化作为HD中一种新的潜在治疗策略。作为一种关键的自噬成分，我们的工作表明SQSTM1的S-酰化可能在神经退行性变中发挥更广泛的作用。
