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SSH1 可抑制 SQSTM1/p62 流和 MAPT/Tau 清除，而不依赖于 CFL（丝切蛋白）的激活。

SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation.

机构信息

USF Health Byrd Institute & Alzheimer Center, Tampa, FL, USA.

Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA.

出版信息

Autophagy. 2021 Sep;17(9):2144-2165. doi: 10.1080/15548627.2020.1816663. Epub 2020 Oct 12.

DOI:10.1080/15548627.2020.1816663
PMID:33044112
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8496729/
Abstract

Accumulation of toxic protein assemblies and damaged mitochondria are key features of neurodegenerative diseases, which arise in large part from clearance defects in the Macroautophagy/autophagy-lysosome system. The autophagy cargo receptor SQSTM1/p62 plays a major role in the clearance of ubiquitinated cargo through Ser403 phosphorylation by multiple kinases. However, no phosphatase is known to physiologically dephosphorylate SQSTM1 on this activating residue. RNAi-mediated knockdown and overexpression experiments using genetically encoded fluorescent reporters and defined mutant constructs in cell lines, primary neurons, and brains show that SSH1, the canonical CFL (cofilin) phosphatase, mediates the dephosphorylation of phospho-Ser403-SQSTM1, thereby impairing SQSTM1 flux and phospho-MAPT/tau clearance. The inhibitory action of SSH1 on SQSTM1 is fully dependent on SQSTM1 Ser403 phosphorylation status and is separable from SSH1-mediated CFL activation. These findings reveal a unique action of SSH1 on SQSTM1 independent of CFL and implicate an inhibitory role of SSH1 in SQSTM1-mediated clearance of autophagic cargo, including phospho-MAPT/tau. : AAV: adeno-associated virus; Aβ42: amyloid β1-42 oligomers; AD: Alzheimer disease; CA3: cornu Ammonis 3; CSNK2/CK2: casein kinase 2; FCCP: 2-[2-[4-(trifluoromethoxy)phenyl]hydrazinylidene]-propanedinitrile; FTLD: frontotemporal lobar degeneration; GFP: green fluorescent protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; SQSTM1/p62: sequestosome-1; PLA: proximity ligation assay; RFP: red fluorescent protein; RIPA: radioimmunoprecipitation assay; shRNA: short hairpin RNA; siRNA: small interfering RNA; Ser403: Serine403; SSH1: slingshot protein phosphatase 1; TBK1: TANK-binding kinase 1; ULK: unc-51 like kinase 1.

摘要

毒性蛋白聚集体和受损线粒体的积累是神经退行性疾病的关键特征，这些疾病在很大程度上是由于巨自噬/自噬溶酶体系统的清除缺陷引起的。自噬货物受体 SQSTM1/p62 通过多种激酶对 Ser403 磷酸化在泛素化货物的清除中起主要作用。然而，目前还不知道有哪种磷酸酶能够在这个激活残基上对 SQSTM1 进行生理去磷酸化。在细胞系、原代神经元和大脑中使用遗传编码荧光报告器和定义的突变构建体进行的 RNAi 介导的敲低和过表达实验表明，SSH1（典型的 CFL（丝切蛋白）磷酸酶）介导磷酸化 Ser403-SQSTM1 的去磷酸化，从而损害 SQSTM1 流和磷酸化 MAPT/tau 的清除。SSH1 对 SQSTM1 的抑制作用完全依赖于 SQSTM1 Ser403 磷酸化状态，并且与 SSH1 介导的 CFL 激活分离。这些发现揭示了 SSH1 对 SQSTM1 的独特作用，独立于 CFL，并暗示了 SSH1 在 SQSTM1 介导的自噬货物清除中的抑制作用，包括磷酸化 MAPT/tau。: AAV：腺相关病毒; Aβ42：淀粉样 β1-42 寡聚物; AD：阿尔茨海默病; CA3：角状 3; CSNK2/CK2：酪蛋白激酶 2; FCCP：2-[2-[4-(三氟甲氧基)苯基]肼基]-丙二腈; FTLD：额颞叶变性; GFP：绿色荧光蛋白; MAP1LC3/LC3：微管相关蛋白 1 轻链 3; SQSTM1/p62：自噬体 1; PLA：接近连接测定; RFP：红色荧光蛋白; RIPA：放射性免疫沉淀测定; shRNA：短发夹 RNA; siRNA：小干扰 RNA; Ser403：丝氨酸 403; SSH1：弹弓蛋白磷酸酶 1; TBK1：TANK 结合激酶 1; ULK：UNC-51 样激酶 1。

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