<br>SQSTM1/p62 的 ALS-FTLD 相关突变破坏选择性自噬和 NFE2L2/NRF2 抗氧化应激途径。,Autophagy

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SQSTM1/p62 的 ALS-FTLD 相关突变破坏选择性自噬和 NFE2L2/NRF2 抗氧化应激途径。
Autophagy ( IF 14.6 ) Pub Date : 2019-07-30 , DOI: 10.1080/15548627.2019.1644076
Zhiqiang Deng _{1,

2,

3} , Junghyun Lim _{1,

4} , Qian Wang ₁ , Kerry Purtell ₁ , Shuai Wu ₅ , Gloria M Palomo ₆ , Haiyan Tan ₇ , Giovanni Manfredi ₆ , Yanxiang Zhao ₅ , Junmin Peng ₇ , Bo Hu ₈ , Shi Chen _{2,

3} , Zhenyu Yue ₁

Affiliation

巨自噬（自噬）是通过不断消化选择性货物来维持蛋白质稳态的关键分解代谢途径。自噬的选择性是由自噬受体介导的，自噬受体识别货物并将其募集到自噬体。SQSTM1/p62 是一种原型自噬受体，常见于与主要神经退行性疾病相关的蛋白质聚集体中。虽然 SQSTM1 的积累涉及选择性自噬途径的紊乱，但导致自噬降解受损的致病机制仍然难以表征。在此，我们表明肌萎缩侧索硬化症（ALS）和 TBK1 和 SQSTM1 的额颞叶变性（FTLD）相关突变破坏选择性自噬并引起神经毒性。我们的数据表明，蛋白毒性应激激活丝氨酸/苏氨酸激酶 TBK1，TBK1 与自噬激酶 ULK1 协调，促进 UBA 结构域自噬受体 SQSTM1 的协同磷酸化和选择性自噬的激活。相比之下，TBK1 或 SQSTM1 的 ALS-FTLD 相关突变会降低 SQSTM1 磷酸化并损害泛素化货物结合和清除。此外，疾病突变 SQSTM1^G427R 消除了 Ser351 的磷酸化并损害了 KEAP1-SQSTM1 相互作用，从而减少了 NFE2L2/Nrf2 靶向基因的表达，并增加了氧化应激下 TARDBP/TDP-43 相关应激颗粒的形成。此外，SQSTM1^G427R 在神经元中的表达会损害树突形态和 KEAP1-NFE2L2 信号传导。因此，我们的结果揭示了致病性 SQSTM1 突变体抑制选择性自噬并破坏 NFE2L2 抗氧化应激反应的机制，这是 ALS-FTLD 神经毒性的基础。

"点击查看英文标题和摘要"

ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway.

Macroautophagy (autophagy) is a key catabolic pathway for the maintenance of proteostasis through constant digestion of selective cargoes. The selectivity of autophagy is mediated by autophagy receptors that recognize and recruit cargoes to autophagosomes. SQSTM1/p62 is a prototype autophagy receptor, which is commonly found in protein aggregates associated with major neurodegenerative diseases. While accumulation of SQSTM1 implicates a disturbance of selective autophagy pathway, the pathogenic mechanism that contributes to impaired autophagy degradation remains poorly characterized. Herein we show that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)-linked mutations of TBK1 and SQSTM1 disrupt selective autophagy and cause neurotoxicity. Our data demonstrates that proteotoxic stress activates serine/threonine kinase TBK1, which coordinates with autophagy kinase ULK1 to promote concerted phosphorylation of autophagy receptor SQSTM1 at the UBA domain and activation of selective autophagy. In contrast, ALS-FTLD-linked mutations of TBK1 or SQSTM1 reduce SQSTM1 phosphorylation and compromise ubiquitinated cargo binding and clearance. Moreover, disease mutation SQSTM1^G427R abolishes phosphorylation of Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43 associated stress granule formation under oxidative stress. Furthermore, expression of SQSTM1^G427R in neurons impairs dendrite morphology and KEAP1-NFE2L2 signaling. Therefore, our results reveal a mechanism whereby pathogenic SQSTM1 mutants inhibit selective autophagy and disrupt NFE2L2 anti-oxidative stress response underlying the neurotoxicity in ALS-FTLD.

更新日期：2019-10-25

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