Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling

Meng-Zhu Li; En-Jie Liu; Qiu-Zhi Zhou; Shi-Hong Li; Shi-Jie Liu; Hai-Tao Yu; Qi-Hang Pan; Qi-Hang Pan; Fei Sun; Ting He; Wei-Jin Wang; Dan Ke; Yu-Qi Feng; Jun Li; Jian-Zhi Wang

doi:10.1186/s40779-022-00396-x

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Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling

RESEARCH | Updated：2023-05-10

- Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
- Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
- Military Medical Research 2023年10卷第2期页码：175-190
- Affiliations：
  
  1.Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  2.Department of Neurosurgery, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
  3.Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
  4.Department of Chemistry, Wuhan University, Wuhan 430072, China
  5.Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226000, Jiangsu, China
- Author bio：
  
  * lj690222@sina.com;
  wangjz@mail.hust.edu.cn
- Funds：
  
  grants from the Natural Science Foundation of China(91949205;31730035;81721005);the Science and Technology Committee of China(2016YFC1305800);the Special Project of Technological Innovation of Hubei Province(2018ACA142);Guangdong Provincial Key S&T Program(2018B030336001)
- DOI：10.1186/s40779-022-00396-x
  中图分类号：
- 纸质出版：2023-04
- Accepted：
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Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling[J]. Military Medical Research, 2023,10(2):175-190.

Cite this article as: Li MZ, Liu EJ, Zhou QZ, Li SH, Liu SJ, Yu HT, et al. Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling. Mil Med Res. 2022;9(1):38.
Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling[J]. Military Medical Research, 2023,10(2):175-190. DOI： 10.1186/s40779-022-00396-x.

Cite this article as: Li MZ, Liu EJ, Zhou QZ, Li SH, Liu SJ, Yu HT, et al. Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling. Mil Med Res. 2022;9(1):38. DOI： 10.1186/s40779-022-00396-x.

摘要

Abstract

Background:

Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.

Methods:

The primary hippocampal neurons

N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy

which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H

-ATPase (v-ATPase) activity

respectively

which were analysed by One‐way ANOVA with post hoc tests. The Western blotting

co-immunoprecipitation and immunofuorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations

as analysed by Student's two-tailed t-test or One‐way ANOVA with post hoc tests. The autophagosome formation was detected by immunofuorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC).

Results:

We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine

=0.0038; Glutamic acid

=0.0348; Alanine

=0.0037; Glycine

=0.0104)

with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1)

0.0001; phosphorylated 70 kD ribosomal protein S6 kinase 1 (p-p70S6K1)

=0.0001

phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1)

=0.0015] and inhibition of autophagosome formation [microtubuleassociated protein light chain 3 II (LC3 II)

=0.0073; LC3 puncta

0.0001]. As expected

this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly

we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1

downregulating the endogenous TIA1 expression by shRNA

or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment.

Conclusions:

Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway

and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treat-ment and that of related tauopathies.

关键词

Keywords

references

Ittner A , Ittner LM . Dendritic tau in Alzheimer's disease . Neuron. 2018 ; 99 ( 1 ): 13 – 27 .

Alonso AC , Zaidi T , Grundke-Iqbal I , Iqbal K . Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease . Proc Natl Acad Sci USA. 1994 ; 91 ( 12 ): 5562 – 6 .

Iqbal K , Grundke-Iqbal I , Zaidi T , Merz PA , Wen GY , Shaikh SS , et al . Defective brain microtubule assembly in Alzheimer's disease . Lancet. 1986 ; 2 ( 8504 ): 421 – 6 .

Kanai Y , Chen J , Hirokawa N . Microtubule bundling by tau proteins in vivo : analysis of functional domains . EMBO J. 1992 ; 11 ( 11 ): 3953 – 61 .

Khatoon S , Grundke-Iqbal I , Iqbal K . Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slotblot assay for nanograms of the protein . J Neurochem. 1992 ; 59 ( 2 ): 750 – 3 .

Yamamori H , Khatoon S , Grundke-Iqbal I , Blennow K , Ewers M , Hampel H , et al . Tau in cerebrospinal fluid: a sensitive sandwich enzyme-linked immunosorbent assay using tyramide signal amplification . Neurosci Lett. 2007 ; 418 ( 2 ): 186 – 9 .

Arriagada PV , Growdon JH , Hedley-Whyte ET , Hyman BT . Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease . Neurology. 1992 ; 42 ( 3 Pt 1 ): 631 – 9 .

Nelson PT , Alafuzoff I , Bigio EH , Bouras C , Braak H , Cairns NJ , et al . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature . J Neuropathol Exp Neurol. 2012 ; 71 ( 5 ): 362 – 81 .

Wu D , Gao D , Yu H , Pi G , Xiong R , Lei H , et al . Medial septum tau accumulation induces spatial memory deficit via disrupting medial septumhippocampus cholinergic pathway . Clin Transl Med. 2021 ; 11 ( 6 ): e428 .

Yin Y , Gao D , Wang Y , Wang ZH , Wang X , Ye J , et al . Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling . Proc Natl Acad Sci USA. 2016 ; 113 ( 26 ): E3773 – 81 .

Zheng J , Li HL , Tian N , Liu F , Wang L , Yin Y , et al . Interneuron accumulation of phosphorylated tau impairs adult hippocampal neurogenesis by suppressing GABAergic transmission . Cell Stem Cell. 2020 ; 26 ( 3 ): 331-45.e6 .

Zheng J , Tian N , Liu F , Zhang Y , Su J , Gao Y , et al . A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies . Signal Transduct Target Ther. 2021 ; 6 ( 1 ): 269 .

Klionsky DJ , Emr SD . Autophagy as a regulated pathway of cellular degradation . Science. 2000 ; 290 ( 5497 ): 1717 – 21 .

Ma Q , Qiang J , Gu P , Wang Y , Geng Y , Wang M . Age-related autophagy alterations in the brain of senescence accelerated mouse prone 8 (SAMP8) mice . Exp Gerontol. 2011 ; 46 ( 7 ): 533 – 41 .

Lipinski MM , Zheng B , Lu T , Yan Z , Py BF , Ng A , et al . Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease . Proc Natl Acad Sci U S A. 2010 ; 107 ( 32 ): 14164 – 9 .

Pickford F , Masliah E , Britschgi M , Lucin K , Narasimhan R , Jaeger PA , et al . The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice . J Clin Investig. 2008 ; 118 ( 6 ): 2190 – 9 .

Hara T , Nakamura K , Matsui M , Yamamoto A , Nakahara Y , Suzuki-Migishima R , et al . Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice . Nature. 2006 ; 441 ( 7095 ): 885 – 9 .

Lim F , Hernandez F , Lucas JJ , Gomez-Ramos P , Moran MA , Avila J . FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain . Mol Cell Neurosci. 2001 ; 18 ( 6 ): 702 – 14 .

Feng Q , Luo Y , Zhang XN , Yang XF , Hong XY , Sun DS , et al . MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration . Autophagy. 2020 ; 16 ( 4 ): 641 – 58 .

Yu L , Chen Y , Tooze SA . Autophagy pathway: Cellular and molecular mechanisms . Autophagy. 2018 ; 14 ( 2 ): 207 – 15 .

Ganley IG , Lam Du H , Wang J , Ding X , Chen S , Jiang X . ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy . J Biol Chem. 2009 ; 284 ( 18 ): 12297 – 305 .

Li X , Alafuzoff I , Soininen H , Winblad B , Pei JJ . Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain . FEBS J. 2005 ; 272 ( 16 ): 4211 – 20 .

Sun YX , Ji X , Mao X , Xie L , Jia J , Galvan V , et al . Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease . J Alzheimers Dis. 2013 ; 38 ( 2 ): 437 – 44 .

Caccamo A , De Pinto V , Messina A , Branca C , Oddo S . Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature . J Neurosci. 2014 ; 34 ( 23 ): 7988 – 98 .

Harrison DE , Strong R , Sharp ZD , Nelson JF , Astle CM , Flurkey K , et al . Rapamycin fed late in life extends lifespan in genetically heterogeneous mice . Nature. 2009 ; 460 ( 7253 ): 392 – 5 .

Zhang Y , Bokov A , Gelfond J , Soto V , Ikeno Y , Hubbard G , et al . Rapamycin extends life and health in C57BL/6 mice . J Gerontol A Biol Sci Med Sci. 2014 ; 69 ( 2 ): 119 – 30 .

Wang W , Zhou Q , Jiang T , Li S , Ye J , Zheng J , et al . A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models . Theranostics. 2021 ; 11 ( 11 ): 5279 – 95 .

Needs SH , Bootman MD , Grotzke JE , Kramer HB , Allman SA . Off-target inhibition of NGLY1 by the polycaspase inhibitor Z-VAD-fmk induces cellular autophagy . FEBS J. 2022 . https://doi.org/10.1111/febs.16345 https://doi.org/10.1111/febs.16345 .

Schmidt EK , Clavarino G , Ceppi M , Pierre P . SUnSET, a nonradioactive method to monitor protein synthesis . Nat Methods. 2009 ; 6 ( 4 ): 275 – 7 .

Panza F , Lozupone M , Logroscino G , Imbimbo BP . A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease . Nat Rev Neurol. 2019 ; 15 ( 2 ): 73 – 88 .

Wu M , Zhang M , Yin X , Chen K , Hu Z , Zhou Q , et al . The role of pathological tau in synaptic dysfunction in Alzheimer's diseases . Transl Neurodegener. 2021 ; 10 ( 1 ): 45 .

Kuang H , Tan CY , Tian HZ , Liu LH , Yang MW , Hong FF , et al . Exploring the bi-directional relationship between autophagy and Alzheimer's disease . CNS Neurosci Ther. 2020 ; 26 ( 2 ): 155 – 66 .

Li HL , Wang HH , Liu SJ , Deng YQ , Zhang YJ , Tian Q , et al . Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration . Proc Natl Acad Sci U S A. 2007 ; 104 ( 9 ): 3591 – 6 .

Liu E , Zhou Q , Xie AJ , Li X , Li M , Ye J , et al . Tau acetylates and stabilizes beta-catenin thereby promoting cell survival . EMBO Rep. 2020 ; 21 ( 3 ): e48328 .

Chang YY , Neufeld TP , Schmid SL . An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation . Mol Biol Cell. 2009 ; 20 ( 7 ): 2004 – 14 .

Hosokawa N , Hara T , Kaizuka T , Kishi C , Takamura A , Miura Y , et al . Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy . Mol Biol Cell. 2009 ; 20 ( 7 ): 1981 – 91 .

Chan EY , Kir S , Tooze SA . siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy . J Biol Chem. 2007 ; 282 ( 35 ): 25464 – 74 .

Itakura E , Mizushima N . Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins . Autophagy. 2014 ; 6 ( 6 ): 764 – 76 .

Adiseshaiah PP , Clogston JD , Mcleland CB , Rodriguez J , Potter TM , Neun BW , et al . Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models . Cancer Lett. 2013 ; 337 ( 2 ): 254 – 65 .

Boland B , Kumar A , Lee S , Platt FM , Wegiel J , Yu WH , et al . Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease . J Neurosci. 2008 ; 28 ( 27 ): 6926 – 37 .

An WL , Cowburn RF , Li L , Braak H , Alafuzoff I , Iqbal K , et al . Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease . Am J Pathol. 2003 ; 163 ( 2 ): 591 – 607 .

Griffin RJ , Moloney A , Kelliher M , Johnston JA , Ravid R , Dockery P , et al . Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology . J Neurochem. 2005 ; 93 ( 1 ): 105 – 17 .

Li X , An WL , Alafuzoff I , Soininen H , Winblad B , Pei JJ . Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain . NeuroReport. 2004 ; 15 ( 14 ): 2237 – 40 .

Kapahi P , Zid BM , Harper T , Koslover D , Sapin V , Benzer S . Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway . Curr Biol. 2004 ; 14 ( 10 ): 885 – 90 .

Powers RW 3rd , Kaeberlein M , Caldwell SD , Kennedy BK , Fields S . Genes Dev. 2006 ; 20 ( 2 ): 174 – 84 .

Maziuk BF , Apicco DJ , Cruz AL , Jiang L , Ash PEA , Da Rocha EL , et al . RNA binding proteins co-localize with small tau inclusions in tauopathy . Acta Neuropathol Commun. 2018 ; 6 ( 1 ): 71 .

Sinsky J , Majerova P , Kovac A , Kotlyar M , Jurisica I , Hanes J . Physiological tau interactome in brain and its link to tauopathies . J Proteome Res. 2020 ; 19 ( 6 ): 2429 – 42 .

Wang P , Joberty G , Buist A , Vanoosthuyse A , Stancu IC , Vasconcelos B , et al . Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo . Acta Neuropathol. 2017 ; 133 ( 5 ): 731 – 49 .

Jewell JL , Kim YC , Russell RC , Yu FX , Park HW , Plouffe SW , et al . Metabolism. Differential regulation of mTORC1 by leucine and glutamine . Science. 2015 ; 347 ( 6218 ): 194 – 8 .

Zoncu R , Bar-Peled L , Efeyan A , Wang S , Sancak Y , Sabatini DM . mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase . Science. 2011 ; 334 ( 6056 ): 678 – 83 .

Sancak Y , Bar-Peled L , Zoncu R , Markhard AL , Nada S , Sabatini DM . Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids . Cell. 2010 ; 141 ( 2 ): 290 – 303 .

Sancak Y , Peterson TR , Shaul YD , Lindquist RA , Thoreen CC , Bar-Peled L , et al . The rag gtpases bind raptor and mediate amino acid signaling to mTORC1 . Science. 2008 ; 320 ( 5882 ): 1496 – 501 .

Evans HT , Benetatos J , Van Roijen M , Bodea LG , Gotz J . Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling . EMBO J. 2019 ; 38 ( 13 ): e101174 .

Vanderweyde T , Apicco DJ , Youmans-Kidder K , Ash PEA , Cook C , Lummertz Da Rocha E , et al . Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity . Cell Rep. 2016 ; 15 ( 7 ): 1455 – 66 .

Gilks N , Kedersha N , Ayodele M , Shen L , Stoecklin G , Dember LM , et al . Stress granule assembly is mediated by prion-like aggregation of TIA-1 . Mol Biol Cell. 2004 ; 15 ( 12 ): 5383 – 98 .

Rayman JB , Kandel ER . TIA-1 is a functional prion-like protein . Cold Spring Harb Perspect Biol. 2017 ; 9 ( 5 ): a030718 .

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