Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain

Mol Cell. 2020 Dec 3;80(5):779-795.e10. doi: 10.1016/j.molcel.2020.10.041. Epub 2020 Nov 17.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / deficiency*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Brain / metabolism*
  • Brain / pathology
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipofuscin / genetics
  • Lipofuscin / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / deficiency*
  • Neoplasm Proteins / metabolism
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquitin / genetics
  • Ubiquitin / metabolism


  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipofuscin
  • Neoplasm Proteins
  • TAX1BP1 protein, human
  • TAX1BP1 protein, mouse
  • Tax1-binding protein 1, rat
  • Ubiquitin