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

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

Author information

1
Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar, India.
2
School of Biotechnology, KIIT University, Bhubaneswar, India.
3
Tumor Microenvironment and Animal Models, Institute of Life Sciences, Bhubaneswar, India.
4
Manipal University, Manipal, India.
5
Immuno-Genomics and Systems Biology, Institute of Life Sciences, Bhubaneswar, India.
6
Molecular Virology and Infectious Diseases, Institute of Life Sciences, Bhubaneswar, India.
7
Translational Research, Institute of Life Sciences, Bhubaneswar, India.
8
Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar, India schauhan@ils.res.in.

Abstract

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

PMID:
30143514
PMCID:
PMC6138442
DOI:
10.15252/embj.201798358
[Indexed for MEDLINE]
Free PMC Article

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