TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy

EMBO J. 2018 Sep 14;37(18):e98358. doi: 10.15252/embj.201798358. Epub 2018 Aug 24.


Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress-induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62-NRF2 axis. We show that TRIM16 is an integral part of the p62-KEAP1-NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress-induced aggregate clearance and protects cells against oxidative/proteotoxic stress-induced toxicity in vitro and in vivo Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation-associated diseases such as neurodegeneration.

Keywords: NRF2; TRIM16; autophagy; p62; protein aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Protein Aggregates*
  • Proteolysis*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitination / genetics


  • ATG16L1 protein, human
  • Autophagy-Related Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • P62 protein, human
  • Protein Aggregates
  • RNA-Binding Proteins
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM16 protein, human
  • Ubiquitin-Protein Ligases
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human