TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy
| Autor: | Santosh Chauhan, Srinivasa Prasad Kolapalli, Pradyumna Kumar Sahoo, Biswajit Das, Parej Nath, Shantibhusan Senapati, Gulam Hussain Syed, Swati Chauhan, Kautilya Kumar Jena, Sunil K. Raghav, Abdul Ahad, Subhash Mehto |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold protein P62/Sqstm1 Protein Homeostasis NF-E2-Related Factor 2 Ubiquitin-Protein Ligases Autophagy-Related Proteins Protein aggregation General Biochemistry Genetics and Molecular Biology Inclusion bodies Tripartite Motif Proteins 03 medical and health sciences Protein Aggregates 0302 clinical medicine Protein Quality Control Ubiquitin Trim16 Autophagy Autophagy-Related Protein-1 Homolog Humans Molecular Biology ATG16L1 Cancer Kelch-Like ECH-Associated Protein 1 Nrf2/Nfe2l2 General Immunology and Microbiology biology General Neuroscience Intracellular Signaling Peptides and Proteins Ubiquitination RNA-Binding Proteins Microreview Aggrephagy Cell biology DNA-Binding Proteins Oxidative Stress 030104 developmental biology Proteostasis HEK293 Cells 030220 oncology & carcinogenesis Multiprotein Complexes Proteolysis biology.protein Proteotoxic Stress Protein folding TRIM Family Microtubule-Associated Proteins HeLa Cells Transcription Factors |
| Zdroj: | Cell Stress |
| ISSN: | 1460-2075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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