MLKL-USP7-UBA52信号通过维持泛素平衡对大脑自噬不可或缺。

Zhigang Zhang, Shuai Chen, Shirui Jun, Xirong Xu, Yuchuan Hong, Xifei Yang, Liangyu Zou, You-Qiang Song, Yu Chen, Jie Tu
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引用次数: 0

摘要

MLKL(类似假激酶的混合系激酶结构域)基因消除的个体对阿尔茨海默病(AD)等神经退行性疾病的易感性增加。然而,其机制尚未完全明了。在这里,我们观察到 mlkl 基因敲除(KO)小鼠大脑中的大自噬/自噬功能明显受损,BECN1/Beclin1 和 ULK1(unc-51 类自噬激活激酶 1)的下调证明了这一点。我们发现 UBA52(泛素 A-52 残基核糖体蛋白融合产物 1)是 MLKL 在生理条件下的结合伙伴。缺失 Mlkl 会阻止 UBA52 的裂解,从而导致泛素水平下降。此外,我们还证明了去泛素酶(DUB)USP7(泛素特异性肽酶 7)介导了 UBA52 的处理过程,而这一过程受 MLKL 的调控。此外,我们的研究结果表明,Mlkl缺失时BECN1和ULK1的减少是由于其赖氨酸63(K63)连接的多泛素化减少所致。此外,单核 RNA 测序显示,Mlkl 缺失导致多种神经退行性疾病相关通路中断,包括与 AD 相关的通路。这些结果与在 mlkl KO 小鼠中观察到的认知障碍以及在缺失 mlkl 的 AD 小鼠模型中观察到的 AD 病理学恶化相一致。综上所述,我们的研究结果表明,MLKL-USP7-UBA52 信号传导需要通过维持泛素平衡来促进大脑自噬,并强调了 Mlkl 缺失诱导的泛素缺陷对神经退行性病变发展的贡献。因此,维持泛素的充足水平可能为通过调节自噬保护个体免受多种神经退行性疾病的侵害提供了一个新的视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.

Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.Abbreviations: 4HB: four-helix bundle; AAV: adeno-associated virus; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aβ: amyloid β; BECN1: beclin 1; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DLG4: discs large MAGUK scaffold protein 4; DUB: deubiquitinase; EBSS: Earle's balanced salt solution; GFAP: glial fibrillary acidic protein; HRP: horseradish peroxidase; IL1B: interleukin 1 beta; IL6: interleukin 6; IPed: immunoprecipitated; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MLKL: mixed lineage kinase domain like pseudokinase; NSA: necrosulfonamide; OPCs: oligodendrocyte precursor cells; PFA: paraformaldehyde; PsKD: pseudo-kinase domain; SYP: synaptophysin; UB: ubiquitin; UBA52: ubiquitin A-52 residue ribosomal protein fusion product 1; UCHL3: ubiquitin C-terminal hydrolase L3; ULK1: unc-51 like autophagy activating kinase 1; UMAP: uniform manifold approximation and projection; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; USP9X: ubiquitin specific peptidase 9 X-linked.

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