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Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

ABSTRACT: Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

SUBMITTER: Caballero B

PROVIDER: S-EPMC8047017 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Caballero Benjamin B Bourdenx Mathieu M Luengo Enrique E Diaz Antonio A Sohn Peter Dongmin PD Chen Xu X Wang Chao C Juste Yves R YR Wegmann Susanne S Patel Bindi B Young Zapporah T ZT Kuo Szu Yu SY Rodriguez-Navarro Jose Antonio JA Shao Hao H Lopez Manuela G MG Karch Celeste M CM Goate Alison M AM Gestwicki Jason E JE Hyman Bradley T BT Gan Li L Cuervo Ana Maria AM

Nature communications 20210414 1

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathway ...[more]

PMID: 33854069

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Project description:RationaleThe NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy (CMA), one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear.ObjectiveTo determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis.Methods and resultsThe expression of CMA marker, LAMP-2A (lysosome-associated membrane protein type 2A), was first analyzed in ApoE-/- mouse aortas and human coronary atherosclerotic plaques, and a significant downregulation of LAMP-2A in advanced atherosclerosis in both mice and humans was observed. To selectively block CMA, we generated macrophage-specific conditional LAMP-2A knockout mouse strains in C57BL/6 mice and ApoE-/- mice. Deletion of macrophage LAMP-2A accelerated atherosclerotic lesion formation in the aortic root and the whole aorta in ApoE-/- mice. Mechanistically, LAMP-2A deficiency promoted NLRP3 inflammasome activation and subsequent release of mature IL (interleukin)-1β in macrophages and atherosclerotic plaques. Furthermore, gain-of-function studies verified that restoration of LAMP-2A levels in LAMP-2A-deficient macrophages greatly attenuated NLRP3 inflammasome activation. Importantly, we identified the NLRP3 protein as a CMA substrate and demonstrated that LAMP-2A deficiency did not affect the NLRP3 mRNA levels but hindered degradation of the NLRP3 protein through CMA pathway.ConclusionsCMA function becomes impaired during the progression of atherosclerosis, which increases NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis progression. Our study unveils a new mechanism by which NLRP3 inflammasome is regulated in macrophages and atherosclerosis, thus providing a new insight into the role of autophagy-lysosomal pathway in atherosclerosis. Pharmacological activation of CMA may provide a novel therapeutic strategy for atherosclerosis and other NLRP3 inflammasome/IL-1β-driven diseases.

Project description:BackgroundLung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression.MethodsWe identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression.ResultsThis study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression.Conclusiono8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment.

Dataset Information

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Publications

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

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