Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain
Autor: | Shireen A. Sarraf, Michael E. Ward, Lynne A. Holtzclaw, Richard J. Youle, Hetal V. Shah, Gil Kanfer, Alicia M. Pickrell |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Male
Cellular homeostasis Aggrephagy Biology Protein aggregation Protein Aggregation Pathological Article Lipofuscin Rats Sprague-Dawley 03 medical and health sciences Mice 0302 clinical medicine Ubiquitin medicine Autophagy Animals Humans Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences Neurodegeneration Intracellular Signaling Peptides and Proteins Brain Neurodegenerative Diseases Cell Biology medicine.disease Cell biology Neoplasm Proteins Rats Proteostasis HEK293 Cells Proteotoxicity biology.protein Female Apoptosis Regulatory Proteins 030217 neurology & neurosurgery HeLa Cells |
Zdroj: | Mol Cell |
Popis: | Summary 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. |
Databáze: | OpenAIRE |
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