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Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria
Open accessAbstract
Significance: Selective autophagy of damaged mitochondria (mitophagy) requires protein kinases PINK1 and TBK1, ubiquitin ligase Parkin, and autophagy receptors such as OPTN, driving ubiquitin-labeled mitochondria into autophagosomes. Because all proteins have been genetically linked to either Parkinson’s disease (PINK1 and Parkin) or amyotrophic lateral sclerosis and frontotemporal lobar degeneration (TBK1 and OPTN), it is of great interest to understand their physiological functions. By utilizing quantitative proteomics we show that TBK1 phosphorylates four receptors on several autophagy-relevant sites. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and activation on mitochondria. TBK1-mediated phosphorylation of OPTN creates a signal amplification loop through combining recruitment and retention of OPTN/TBK1 on ubiquitinated mitochondria.
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“Through its phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) [58,59,194], TBK1 regulates several aspects of autophagy, including macroautophagy, xenophagy and mitophagy [59,90,148,194–196].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [194]
In the citing paper
“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 [194]
In the citing paper
“Mitochondrial protein ubiquitination promotes mitochondrial recruitment of autophagy regulators and receptors such as TBK1 and optineurin (Heo et al., 2015, Matsumoto et al., 2015, Richter et al., 2016).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Richter et al., 2016
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“The latter phosphorylates these receptors, including OPTN, NDP52 [98], and SQSTM1/p62 [99].”
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“Phosphorylation of OPTN at Ser177 facilitates its binding with Atg8 family of proteins, while phosphorylation at Ser residues 473 and 513 in its ubiquitin-binding region enhances its binding with Ub chains (Heo et al., 2015; Moore and Holzbaur 2016; Richter et al., 2016).”
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VPS4A is the selective receptor for lipophagy in mice and humans
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“TBK1 promotes the autophagic degradation of BinCARD1 by activating p62 phosphorylation TBK1 can regulate autophagy by phosphorylating the autophagy receptors OPTN and p62 [54, 55].”
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“TBK1 also participates in autophagy through phosphorylation of autophagy receptor proteins (Richter et al., 2016; Durand et al., 2018).”
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“Proteins such as OPTN, NDP52, or p62 thus condition the possibility of coating and preparing marked mitochondria for degradation [72,73].”
BackgroundTBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877
Antonia, R. J., Cabrera, J. C., Herring, L. E., Serafín, D., Liu, P., Graves, L. M., Baldwin, A. S., & Hagan, R. S. (2019) · Scientific Reports · doi:10.1038/s41598-019-49707-8 · Cited by 42
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“In the current mitophagy model, OPTN and NDP52 recruit phagophores to mitochondria by directly binding to LC3 through their LC3-interacting region (LIR), after binding to polyubiquitin chains [55,56].”
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“Ser177 phosphorylation in OPTN is known for ATG8 recruitment, while the dual phosphorylation of Ser473 and Ser513 activates polyubiquitin chain binding of OPTN, followed by the facilitated activation of TBK1 in vivo, as well as OPTN retention on damaged mitochondria, and mitophagy (124, 125).”
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“Thus, p62 is thought to play a secondary role inmitophagy, while as primary mitophagic receptors, OPTN and NDP52 have been identified (Wong and Holzbaur 2014; Heo et al., 2015; Lazarou et al., 2015; Richter et al., 2016).”
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“Furthermore, Richter et al.80 demonstrated that phospho-ubiquitin chains interact with phosphorylated OPTN to promote selective autophagy of damaged mitochondria.”
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“Next we asked if BNIP3/NIX require activation by a kinase, such as TBK1, which is known to phosphorylate soluble cargo receptors and cargo co-receptors to enhance their LC3-binding capacities 40,41 .”
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“The recruitment of OPTN to mitochondria activates TANK-binding kinase 1 (TBK1), which further phosphorylates OPTN and increases mitophagy [60].”
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A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy
Tudorica, D. A., Basak, B., Cordova, A. S. P., Khuu, G., Rose, K. M., Lazarou, M., Holzbaur, E. L. F., & Hurley, J. H. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202309015 · Cited by 31
Das, S., Murumulla, L., Ghosh, P., & Challa, S. (2025) · BioMetals · doi:10.1007/s10534-025-00665-x · Cited by 30
“Disease-associated mutations in SQSTM1 or TBK1 reduce selective autophagy by decreasing SQSTM1 phosphorylation, impairing its interaction with KEAP1, and curtailing the NFE2L2/NRF2-mediated oxidative stress response, which enhances TARDBP/TDP-43 aggregate formation and contributes to neurotoxicity in ALS-FTD (Richter…”
Hidden phenotypes of PINK1/Parkin knockout mice
Paul, S., & Pickrell, A. M. (2021) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2021.129871 · Cited by 31
Autophagy in the eye: from physiology to pathophysiology
Liton, P. B., Boesze‐Battaglia, K., Boulton, M. E., Boya, P., Ferguson, T. A., Ganley, I. G., Kauppinen, A., Laurie, G. W., Mizushima, N., Morishita, H., et al. (2023) · Autophagy Reports · doi:10.1080/27694127.2023.2178996 · Cited by 31
Skeletal muscle mitophagy in chronic disease
Leermakers, P. A., & Gosker, H. R. (2016) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000319 · Cited by 31
Foster, A., Downing, P., Figredo, E., Polain, N., Stott, A., Layfield, R., & Rea, S. L. (2020) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2020.103539 · Cited by 29
Platelet biomarkers identifying mild cognitive impairment in type 2 diabetes patients
Yu, H., Liu, Y., He, T., Zhang, Y., He, J., Li, M., Jiang, B., Gao, Y., Chen, C., Ke, D., et al. (2021) · Aging Cell · doi:10.1111/acel.13469 · Cited by 28
ATG8ylation of proteins: A way to cope with cell stress?
Carosi, J. M., Nguyen, T. N., Lazarou, M., Kumar, S., & Sargeant, T. J. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202108120 · Cited by 30
Zhang, Y., Li, T., Cai, X., Long, D., Wang, X., Liu, C., & Wu, Q. E. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00861-5 · Cited by 29
“OPTN contributes to both the formation of autophagosomes [15, 16] and the autophagosomelysosome fusion [18] stage in autophagic flux.”
BackgroundThe Role of PTEN-L in Modulating PINK1-Parkin-Mediated Mitophagy
Eldeeb, M. A., Esmaili, M., Hassan, M., & Ragheb, M. A. (2022) · Neurotoxicity Research · doi:10.1007/s12640-022-00475-w · Cited by 30
“In the presence of PINK1 and Parkin, TBK1 activation also requires OPTN binding to Ub chains (Heo et al. 2015; Richter et al. 2016).”
BackgroundInterplay between Autophagy and Herpes Simplex Virus Type 1: ICP34.5, One of the Main Actors
Ripa, I., Andreu, S., López‐Guerrero, J. A., & Bello‐Morales, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113643 · Cited by 28
The TMEM192-mKeima probe specifically assays lysophagy and reveals its initial steps
Shima, T., Ogura, M., Matsuda, R., Nakamura, S., Jin, N., Yoshimori, T., & Kuma, A. (2023) · Journal of Cell Biology · doi:10.1083/jcb.202204048 · Cited by 24
Roles of mitophagy in cellular physiology and development
Dengjel, J., & Abeliovich, H. (2016) · Cell and Tissue Research · doi:10.1007/s00441-016-2472-0 · Cited by 28
Benson, B. C., Shaw, P. J., Azzouz, M., Highley, J. R., & Hautbergue, G. M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.783624 · Cited by 30
“It is important to note that ALS-TDP proteinopathies are linked with mutations in genes such as TBK1 with functions other than protein degradation pathways, indicating that failures in these systems are not the only route to degeneration.”
BackgroundInfluentialDavidson, J. M., Chung, R. S., & Lee, A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105653 · Cited by 29
“TBK1 also phosphorylates and regulates the activity of OPTN, a receptor that binds ubiquitylated chains for selective autophagy of damaged mitochondria and interacts with p62 (Richter et al., 2016).”
BackgroundOptineurin Functions for Optimal Immunity
Slowicka, K., & Loo, G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00769 · Cited by 32
“The ALS-associated TBK1 E696K mutation specifically abolishes its binding to OPTN and disrupts OPTN/TBK1 complex formation (23, 34), this in contrast to the glaucoma-associated OPTN E50K mutation, shown to cause death of retinal ganglion cells in vitro and in transgenic mice (35), which enhances the interaction betwee…”
BackgroundInfluentialCell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS
Yamashita, T., & Kwak, S. (2018) · Neuroscience Research · doi:10.1016/j.neures.2018.06.004 · Cited by 28
Fu, Y., Zhang, J., Qin, R., Ren, Y., Zhou, T., Han, B., & Liu, B. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100053 · Cited by 29
New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease
Xin, Y., Zhang, X., Li, J., Gao, H., Li, J., Li, J., Hu, W., & Li, H. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.774619 · Cited by 28
Regulation of neuronal autophagy and cell survival by MCL1 in Alzheimer’s disease
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“0 International License proteins of OMM; consequently, a feed-forward loop forms, which enhances the modification of OMM with pUb-chains and provides binding platforms for autophagy receptors, such as optineurin (OPTN), nuclear domain 10 protein 52 (NDP52), and Tax1-binding protein 1 (TAX1BP1) [33, 38, 39].”
BackgroundInfluentialMechanistic Insights into Recognitions of Ubiquitin and Myosin VI by Autophagy Receptor TAX1BP1
Hu, S., Wang, Y., Gong, Y., Liu, J., Li, Y., & Pan, L. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.06.030 · Cited by 27
Wu, W., Yuan, S., Tang, Y., Meng, X., Peng, M., Hu, Z., & Liu, W. (2023) · Nutrients · doi:10.3390/nu15132851 · Cited by 33
“TBK1 activity is required for efficient recruitment of OPTN and NDP52 to ubiquitinated mitochondria, where TBK1 phosphorylates OPTN at Ser177 to increase the LC3 binding affinity and at Ser473 and Ser513 to further increase binding of OPTN to the ubiquitin chain [101,102].”
BackgroundThe Role of Mitophagy in Glaucomatous Neurodegeneration
Stavropoulos, D., Grewal, M. K., Petriti, B., Chau, K., Hammond, C. J., Garway‐Heath, D. F., & Lascaratos, G. (2023) · Cells · doi:10.3390/cells12151969 · Cited by 27
Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival
Zein, L., Dietrich, M., Balta, D., Bader, V., Scheuer, C., Zellner, S., Weinelt, N., Vandrey, J., Mari, M. C., Behrends, C., et al. (2025) · Autophagy · doi:10.1080/15548627.2024.2443945 · Cited by 31
“Apart from its roles played in lysophagy, TBK1 also regulates other forms of selective autophagy by phosphorylating autophagy receptors such as OPTN, CALCOCO2/NDP52, TAX1BP1 and SQSTM1/p62 to regulate ubiquitin and LC3 binding [32,34,76,77].”
Selective autophagy: The new player in the fight against neurodegenerative diseases?
Wu, M.-Y., Song, J., Wang, S.-F., Cai, C.-Z., Li, M., & Lu, J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.11.009 · Cited by 27
“Recently, TANK-binding kinase 1 (TBK1) has been shown to phosphorylate all the receptors (OPTN, NDP52, TAX1BP1, and p62) involved in mitophagy (Richter et al., 2016).”
BackgroundThe Selective Autophagy Receptor Optineurin in Crohn’s Disease
Tschurtschenthaler, M., & Adolph, T. E. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00766 · Cited by 27
“Before autophagic clearance of the ubiquitinated cargo, TBK1 activates OPTN by phosphorylation in order to enhance its binding capacity to LC3, a conjugate of the autophagosomal membrane (38, 40).”
BackgroundAutophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act
Jiménez-Moreno, N., & Lane, J. D. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8865611 · Cited by 26
“For example, receptor binding affinity (particularly OPTN and p62/SQSTM1) is increased via phosphorylation by tankbinding kinase 1 (TBK1) [141, 142].”
BackgroundAberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis
Zhang, Y., Gu, J., & Sun, Q. (2021) · Cells · doi:10.3390/cells10092247 · Cited by 28
New insights into the structure of PINK1 and the mechanism of ubiquitin phosphorylation
Rasool, S., & Trempe, J. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1491525 · Cited by 26
“ubiquitin-like proteins LC3B and LC3C, resulting in the recruitment of autophagy machinery to the mitochondria (Heo et al. 2015; Lazarou et al. 2015; Moore and Holzbaur 2016; Richter et al. 2016).”
BackgroundMolecular Recognition of M1-Linked Ubiquitin Chains by Native and Phosphorylated UBAN Domains
Herhaus, L., van den Bedem, H., Tang, S., Maslennikov, I., Wakatsuki, S., Đikić, I., & Rahighi, S. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.06.012 · Cited by 27
Self-citationHo, P., Hsieh, T., & Tsai, K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102441 · Cited by 28
“…including macroautophagy, xenophagy, and mitophagy, by phosphorylating autophagy receptors such as optineurin, SQSTM1, and calcium-binding and coiled-coil domain 2 (Heo et al., 2015; Loo and Gale, 2011; Matsumoto et al., 2015; Pilli et al., 2012; Richter et al., 2016; Sellier et al., 2016).”
BackgroundZhang, Y., Varela, L., Szigeti‐Buck, K., Williams, A., Stoiljković, M., Šestan-Peša, M., Henao‐Mejia, J., D’Acunzo, P., Levy, E., Flavell, R. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22003-8 · Cited by 25
Regulation of mitochondrial cargo-selective autophagy by posttranslational modifications
Lechado‐Terradas, A., Zittlau, K. I., Maček, B., Fraiberg, M., Elazar, Z., & Kahle, P. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101339 · Cited by 27
“Moreover, TBK1-catalyzed phosphorylation of S177—near the optineurin LIR motif—stabilizes the binding of optineurin to ubiquitylated mitochondria (39, 194), in addition to an influence on LC3 recruitment (193).”
BackgroundChen, W., Guo, L., Li, M., Wei, C., Li, S., & Xu, R. (2022) · Brain Research · doi:10.1016/j.brainres.2022.147904 · Cited by 26
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Metadata
- Authors
- Richter, B., Sliter, D. A., Herhaus, L., Stolz, A., Wang, C., Beli, P., Zaffagnini, G., Wild, P., Martens, S., Wagner, S. A., Youle, R. J., & Dikic, I.
- Affiliations
- Goethe University Frankfurt (DE)
- National Institutes of Health (US)
- Institute of Molecular Biology (DE)
- University of Vienna (AT)
- Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt, Germany;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-03-30
- Volume
- 113
- Issue
- 15
- Pages
- 4039-4044
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4839414
- OpenAlex
- W2323582440
- Cited by
- 755
- References
- 44
- Citations by year
- 2026: 64 · 2025: 69 · 2024: 71 · 2023: 56 · 2022: 80 · 2021: 95 · 2020: 82 · 2019: 74 · 2018: 77 · 2017: 60 · 2016: 27
- FWCI
- 74.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DI 931/3-1)
- Cluster of Excellence (EXC115)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- optineurin, TBK1, phosphorylation, selective autophagy, mitophagy, damaged mitochondria, ubiquitin chains, autophagy receptors, NDP52, TAX1BP1, p62, PINK1, Parkin, signal amplification
- MeSH terms
- Autophagy, HeLa Cells, Humans, Mitochondria, Phosphorylation, Protein Binding, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ubiquitin, Membrane Transport Proteins, Transcription Factor TFIIIA
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