Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain.
Mol Cell
; 80(5): 779-795.e10, 2020 12 03.
Article
em En
| MEDLINE
| ID: mdl-33207181
ABSTRACT
Protein aggregates disrupt cellular homeostasis, causing toxicity linked to neurodegeneration. Selective autophagic elimination of aggregates is critical to protein quality control, but how aggregates are selectively targeted for degradation is unclear. We compared the requirements for autophagy receptor proteins OPTN, NBR1, p62, NDP52, and TAX1BP1 in clearance of proteotoxic aggregates. Endogenous TAX1BP1 is recruited to and required for the clearance of stress-induced aggregates, whereas ectopic expression of TAX1BP1 increases clearance through autophagy, promoting viability of human induced pluripotent stem cell-derived neurons. In contrast, TAX1BP1 depletion sensitizes cells to several forms of aggregate-induced proteotoxicity. Furthermore, TAX1BP1 is more specifically expressed in the brain compared to other autophagy receptor proteins. In vivo, loss of TAX1BP1 results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains of young TAX1BP1 knockout mice. TAX1BP1 mediates clearance of a broad range of cytotoxic proteins indicating therapeutic potential in neurodegenerative diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Encéfalo
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Doenças Neurodegenerativas
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteínas Reguladoras de Apoptose
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Agregação Patológica de Proteínas
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Proteínas de Neoplasias
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Mol Cell
Ano de publicação:
2020
Tipo de documento:
Article