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Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Open accessAbstract
Summary: Aggregation of misfolded proteins and the associated loss of neurons are considered a hallmark of numerous neurodegenerative diseases. Optineurin is present in protein inclusions observed in various neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob disease and Pick's disease. Optineurin deletion mutations have also been described in ALS patients. However, the role of optineurin in mechanisms of protein aggregation remains unclear. In this report, we demonstrate that optineurin recognizes various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increases protein aggregation in HeLa cells and that morpholino-silencing of the optineurin ortholog in zebrafish causes the motor axonopathy phenotype similar to a zebrafish model of ALS. A more severe phenotype is observed when optineurin is depleted in zebrafish carrying ALS mutations. Furthermore, TANK1 binding kinase 1 (TBK1) is colocalized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at serine 177 and regulates its ability to interact with autophagy modifiers. This study provides evidence for a ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates as well as additional relevance for TBK1 as an upstream regulator of the autophagic pathway.
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“OPTN is an autophagy receptor that binds ubiquitinated cargo (via its UBAN domain) and LC3 (via its LIR domain) [194,254,255], although it can also act independently of target ubiquitination [254].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [254]
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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
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Metadata
- Authors
- Korac, J., Schaeffer, V., Kovacevic, I., Clement, A. M., Jungblut, B., Behl, C., Terzic, J., & Dikic, I.
- Affiliations
- Department of Immunology and Medical Genetics, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
- Institute of Biochemistry II and Buchmann Institute for Molecular Life Sciences, School of Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt (Main), Germany
- Johannes Gutenberg University Mainz (DE)
- Max Planck Institute for Heart and Lung Research (DE)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2013-01-15
- Volume
- 126
- Issue
- 2
- Pages
- 580-592
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC3654196
- OpenAlex
- W1985484942
- Cited by
- 336
- References
- 54
- Citations by year
- 2026: 6 · 2025: 21 · 2024: 25 · 2023: 15 · 2022: 25 · 2021: 25 · 2020: 35 · 2019: 31 · 2018: 25 · 2017: 26 · 2016: 35 · 2015: 37 · 2014: 20 · 2013: 10
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- optineurin, TBK1, protein aggregation, autophagy-lysosome pathway, coiled-coil domain, neurodegenerative diseases, amyotrophic lateral sclerosis, zebrafish model, TBK1 phosphorylation, protein inclusions
- MeSH terms
- Animals, Autophagy, Disease Models, Animal, HeLa Cells, Humans, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Protein Binding, Zebrafish, Cell Cycle Proteins, Neurodegenerative Diseases, Ubiquitin, Membrane Transport Proteins, Transcription Factor TFIIIA, Mice
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