DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins
DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins
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DOI：
10.1038/s41418-024-01261-1
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发表时间：
2024-02-08
影响因子：
12.4
通讯作者：
Wang，Chenji
中科院分区：
文献类型：
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作者：
Jia，Fei;Wang，Xiaoman;Wang，Chenji
遗传性痉挛性截瘫（HSP）是一组以进行性下肢痉挛和无力为特征的遗传性神经退行性疾病。 HSP 的一种亚型称为 SPG54，是由 DDHD2 基因的双等位基因突变引起的。在 SPG54 患者中观察到的主要病理特征是大脑中脂滴 (LD) 的大量积累。然而，DDHD2 在调节脂质稳态中的确切机制和作用尚未完全清楚。通过亲和纯化质谱 (AP-MS) 分析，我们发现 DDHD2 与 ATG8 家族蛋白（LC3、GABARAP）的多个成员相互作用，这些成员在脂肪自噬中发挥着至关重要的作用。突变分析揭示了 DDHD2 蛋白中存在两个真实的 LIR 基序，这对于其与 LC3/GABARAP 的结合至关重要。我们发现，DDHD2 缺陷会导致 LD 积累，而 DDHD2 表达增强会减少 LD 形成。 DDHD2 的 LC3/GABARAP 结合能力和经典自噬途径都有助于其 LD 消除活性。此外，DDHD2 增强了 LC3B 和 LD 之间的共定位，以促进脂肪自噬。 LD·ATTEC 是一种将 LC3 与 LD 结合以增强其自噬清除能力的小分子，可有效抵消 DDHD2 缺陷引起的 LD 积累。这些发现为了解 DDHD2 在 LD 分解代谢中的调节作用提供了有价值的见解，并为治疗 SPG54 患者提供了潜在的治疗方法。
Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in theDDHD2gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathway both contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.