Molecular Cell
Volume 80, Issue 5, 3 December 2020, Pages 779-795.e10
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Article
Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain

https://doi.org/10.1016/j.molcel.2020.10.041Get rights and content
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Highlights

  • Loss of TAX1BP1 blocks clearance of protein aggregates in cells

  • Increased expression of TAX1BP1 promotes aggregate clearance via autophagy

  • Aggregate clearance is ubiquitin dependent

  • Mice lacking functional TAX1BP1 accumulate ubiquitin conjugates in the brain

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.

Keywords

selective autophagy
aggrephagy
p62
Huntington’s disease
aggregate
autophagy receptor
ubiquitin
proteostasis
proteotoxic stress
OPTN

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