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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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“…uncovered that EV-encoded proteinases target several autophagy receptor proteins, including sequestosome 1/ p62, neighbor of BRCA1 (NBR1), and NDP52 to evade the host’s effort in degrading viral particles and its components, termed as virophagy (Shi et al., 2013, 2014; Mohamud et al., 2019).”
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Houghton, O. H., Mizielinska, S., & Gómez‐Suaga, P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.838402 · Cited by 12
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“TBK1 has been associated with selective autophagy receptors such as OPTN [64], CALCOCO2 [52,65], and SQSTM1 [29,50]; however, other studies have suggested a more generalized role in autophagosome maturation [66] or trafficking events associated with ATG9A (autophagy related 9A) [67].”
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“[11,31,32,60,67] Recently, METTL23 has been shown to catalyze the dimethylation of H3R17 and upregulate SP2 transcription both in vitro and in vivo , along with TNF‑ α and IL‑1 β in vivo .”
BackgroundRCHY1 and OPTN are required for melanophagy, selective autophagy of melanosomes
Lee, K. W., Ryu, K., Kim, M., Lim, S., Kim, J., Kim, J. Y., Hwangbo, C., Yoo, J., Cho, Y., & Kim, K. D. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2318039121 · Cited by 12
“TBK1 - mediated OPTN phos phorylation is reportedly required for mitophagy (24).”
BackgroundAutophagy Dysfunction and Neurodegeneration: Where Does It Go Wrong?
Oettinger, D., & Yamamoto, A. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169219 · Cited by 10
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“Phosphorylation of OPTN at S177, which was only phosphorylated 3 hours following sprint-interval exercise, has been shown to promote mitophagy [65] and to be involved in selective autophagy [66] ( ▶ Figs.”
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“Activation of this cycle promotes the downstream assembly of the rest of the mitophagy machinery, as TBK1 can phosphorylate autophagy proteins to increase their affinity for autophagy substrates [108] or to promote their assembly and activation [105,109–112].”
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“TBK1 and IKK ε activation induces autophagic flux by activating autophagy receptors ( 33 – 35 ), and autophagy has been previously proposed as a mechanism of NLRP3 removal ( 36 ), as well as removal of damaged organelles ( 37 ).”
Levi-D’Ancona, E., Walker, E. M., Zhu, J., Deng, Y., Sidarala, V., Stendahl, A. M., Reck, E. C., Henry-Kanarek, B. A., Lietzke, A. C., Chai, B., et al. (2025) · Science Advances · doi:10.1126/sciadv.adw4153 · Cited by 10
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“Phosphorylation of OPTN by TANK-binding kinase 1 (TBK1) enhanced its binding to LC3 and Ub chains [113,115], while phosphorylation of NDP52 by TBK1 enhanced the interaction with the FIP200/ULK1 complex, though this effect was not essential [116].”
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“For example, during mitophagy, TAX1BP1, optineurin, and NDP52 have been found to be necessary for TBK1 activation (Heo et al., 2015; Lazarou et al., 2015; Moore and Holzbaur, 2016; Richter et al., 2016).”
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“TBK1 promotes substrate recruitment to autophagosomes by phosphorylating autophagy adaptors and enhances adaptor binding to polyubiquitin [116,117].”
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“We previously reported that HPC activates Parkin via modulating PINK1 signaling after tGCI.”
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“PINK1 and (phospho)ubiquitin chains on the MOM proteins further amplify the autophagy signal by recruiting specific autophagy receptors [82] such as optineurin [83], NDP52 [84], SQSTM1 [85], and HDAC6 [86], leading to selective engulfment of damaged mitochondria by phagophores.”
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“The lysine residue introduced to OPTN as a result of E50K mutation forms tight ionic interaction with the E698 residue in TBK1 kinase resulting in insoluble aggregates [146,147], potentially inhibiting OPTN function.”
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“, 2010) and also acts as a scaffold for ubiquitin binding autophagy adaptor proteins to tether mitochondria to the developing autophagophore (Heo et al., 2015; Lazarou et al., 2015; Richter et al., 2016; Wong and Holzbaur, 2014).”
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Mammalian innate antiviral defenses: beyond interferon
Rex, E. A., Shaffer, J., Deng, D. M., & Gammon, D. B. (2025) · Journal of Virology · doi:10.1128/jvi.01707-24 · Cited by 7
“Through a process called “virophagy , ” autophagy selectively In addition to canonical IFN pathways (120, 139–142), cGAS-STING (143, 144), NF-κB (145–147), and eIF2α kinase signaling (141, 148, 149) pathways influence autophagy activation in an IFN-I-independent manner (Fig.”
Zhang, X., Zhang, S., & Wang, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262210907 · Cited by 5
“TBK1 specifically phosphorylates S13 and S16 [46], and also phosphorylates key components of the autophagy pathway, including OPTN, p62/SQSTM1, NDP52, and TAX1BP1 [61].”
Self-citationZhi, F., Fan, T., Zhang, Y., Chen, P., He, S., Li, X., Zhang, S., He, J., Shen, X., Bao, C., et al. (2025) · The Plant Cell · doi:10.1093/plcell/koaf284 · Cited by 5
Chen, J., Chu, X., Wu, Y., Su, L., Wang, M., Zhao, X., Wei, X., Xia, G., Xia, H., Lin, S., et al. (2026) · Neoplasia · doi:10.1016/j.neo.2026.101291 · Cited by 5
“Importantly, OPTN and NDP52 can translocate to the OMM independent of Parkin, highlighting their critical roles in Parkin-deficient neurons [112,113].”
STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy
Huang, Z.-B., Lin, J.-Y., Cheng, L.-J., Wu, Y., Gao, X.-Z., Zhang, Y., He, G.-L., Ling, H.-Y., Tan, H. W. S., Guo, Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117515 · Cited by 5
Self-citationHuman Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview
Gorący, A., Rosik, J., Szostak, B., Ustianowski, Ł., Ustianowska, K., & Gorący, J. (2022) · Viruses · doi:10.3390/v14051092 · Cited by 5
Liu, H., Li, H., Zhang, J., Meng, Q., & Ma, L. (2022) · Medicine · doi:10.1097/md.0000000000029996 · Cited by 5
“Tank-binding kinase (TBK1) is a kind of atypical IκB kinases interacting with multiple substrates.[5] Numerous studies show that TBK1 plays important roles in the process of inflammatory response, autophagy, and cell death.”
BackgroundWen, D., Li, Q., Li, Y., Yan, W., Wang, Y., & Liu, Y. (2025) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2025.07.011 · Cited by 5
“TBK1 phosphorylates the autophagy cargo receptor OPTN at S177 to regulate autophagy and mitophagy (Matsumoto et al., 2015; Richter et al., 2016).”
PAWI-2: A novel inhibitor for eradication of cancer
Cheng, J., & Cashman, J. R. (2020) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02575-8 · Cited by 5
“TBK1 is involved in tumor suppression via a mitophagy pathway (Richter et al. 2016).”
BackgroundOptineurin Dysfunction in Amyotrophic Lateral Sclerosis: Why So Puzzling?
Prtenjača, N. (2020) · Periodicum Biologorum · doi:10.18054/pb.v121-122i1-2.10627 · Cited by 5
“To enhance its binding to both LC3 and the ubiquitinated cargo, optineurin must be phosphorylated by TBK1 on Ser177 and Ser473 (3, 66).”
BackgroundDetermination of cytoplasmic optineurin foci sizes using image correlation spectroscopy
Kitamura, A., Shimizu, H., & Kinjo, M. (2018) · The Journal of Biochemistry · doi:10.1093/jb/mvy044 · Cited by 5
“As OPTN is involved in vesicular trafficking and mitophagy in the cytoplasm (19, 23), the intermediate fusion and fission of the membrane vesicle containing OPTN may be visualized.”
BackgroundPINK1 , parkin, and autophagy receptors: A new model of mitophagy
Olszewska, D. A., & Lynch, T. (2016) · Movement Disorders · doi:10.1002/mds.26812 · Cited by 5
“PINK1 and parkin mutations disrupt this process, and autophagy receptors mutations cause neurodegeneration.(1) However, the precise function of autophagy receptors remains unclear, and their role in cellular “waste”
BackgroundBotella, J., Perri, E., Caruana, N. J., López-Calcerrada, S., Brischigliaro, M., Jamnick, N. A., Oorschot, V. M. J., Saner, N. J., Díaz‐Lara, J., Taylor, D. F., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.19.629456 · Cited by 5
Zhang, Y., Li, C., Zhang, M., Qi, S., & Kong, X. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.144309 · Cited by 4
TNIP1 and autophagy receptors regulate STING signaling
Bunker, E. N., Fischer, T. D., Zhu, P.-P., Guerroué, F. L., Johnson, K. R., & Youle, R. J. (2025) · Molecular Biology of the Cell · doi:10.1091/mbc.e25-04-0190 · Cited by 4
Self-citationSun, S., Xin, J., Zhang, Y., Yang, B., Su, D., Ni, R., Ma, Q., Li, N., Ma, G., Peng, Q., et al. (2026) · Aging Cell · doi:10.1111/acel.70402 · Cited by 4
Hepatitis C Virus NS5A Activates Mitophagy Through Cargo Receptor and Phagophore Formation
Hsiao, Y.-C., Chang, C.-W., Yeh, C., & Ke, P. (2024) · Pathogens · doi:10.3390/pathogens13121139 · Cited by 4
Beyond interferons: Non-canonical roles of MITA/STING
Zhang, L., Zhang, C., & Zhang, J. (2025) · Cell Insight · doi:10.1016/j.cellin.2025.100266 · Cited by 4
“TBK1 phosphorylates optineurin (OPTN) and p62/SQSTM1, which are critical for autophagy and also genetically linked to ALS (Cirulli et al., 2015; Matsumoto et al., 2015; Richter et al., 2016).”
Okatsu, K., Kikuchi, R., Matsuda, N., Fukai, S., & Yamano, K. (2025) · Genes to Cells · doi:10.1111/gtc.70043 · Cited by 4
Targeting macroautophagy to combat neurodegenerative disease: strategies and considerations
Duncan, G. M., & Yamamoto, A. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2571940 · Cited by 6
“Loss-of-function mutations in TBK1 as well as OPTN and SQSTM1/p62 has also been identified for ALS[3], thereby making it and PD two disorders in which cargo capture, especially of mitochondria, might be specifically dysregulated [8,93,95] .”
Li, X., Yu, F., Fu, C., Yu, X., Xu, M., & Cheng, M. (2021) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.202100019 · Cited by 4
Novel insights into the pathological features of COPD: Focus on oxidative stress and mitophagy
Gao, J., Shen, Y., & Chen, Z. H. (2024) · Clinical and Translational Discovery · doi:10.1002/ctd2.343 · Cited by 4
“30,31 Recent studies have demonstrated that cell cycle protein G-associated kinase (GAK) and protein kinase C delta (PRKCD) act as positive regulators of PRKN-independent mitochondrial autophagy.”
Dash, B. K., Urano, Y., & Noguchi, N. (2024) · Redox Experimental Medicine · doi:10.1530/rem-24-0014 · Cited by 4
Khoshnood, B., Ullgren, A., Laffita‐Mesa, J. M., Öijerstedt, L., Patra, K., Nennesmo, I., & Graff, C. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10887-x · Cited by 4
“05), which is in line with previous reports about the role of TBK1 in regulation of mitophagy [35].”
Resultvan der Heide, C. J., Miller, M. A., & Fingert, J. H. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816222-4.00007-1 · Cited by 4
PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathyPreprint
Lee, S., Jeon, Y., Kim, S., Kwon, Y., Jo, M., Jang, Y.-N., Lee, S., Kim, J., Kim, S. R., Lee, K. J., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/355446 · Cited by 4
Mauthe, M., & Reggiori, F. (2017) · Microbial Cell · doi:10.15698/mic2017.01.550 · Cited by 3
“In particular, phosphorylation of OPTN by TBK1 promotes selective sequestration of microbes as well as mitochondria [6].”
Bae, J., You, C., Jeong, Y., Kim, J., Lee, J., Jeong, H., Kim, H., Vuong, T. A., Gwon, Y., Bae, G., et al. (2025) · Autophagy · doi:10.1080/15548627.2025.2551477 · Cited by 3
“TBK1, in turn, phosphorylates autophagy receptors, with TBK1-mediated phosphorylation of OPTN promoting the selective autophagy of damaged mitochondria [25].”
Herrera, M. G., Kühn, L., Jungbluth, L., Bader, V., Krause, L. J., Kartte, D., Adriaenssens, E., Martens, S., Tatzelt, J., Sachse, C., et al. (2025) · Advanced Science · doi:10.1002/advs.202509927 · Cited by 3
Self-citationMao, B.-H., Su, B.-K., Wang, Y., & Tu, T. (2026) · Advanced Science · doi:10.1002/advs.202519792 · Cited by 3
“DUBs like USP34 and the facilitator USP8 prune these chains to calibrate receptor engagement, while TANK-binding kinase 1 (TBK1) phosphorylates cargo adaptors such as OPTN to boost their ubiquitin and LC3-binding affinities, potentiating mitophagic flux [ 227 ].”
Manganelli, F., Perfetto, C., Carletta, O., & Gerbino, V. (2026) · Cells · doi:10.3390/cells15050477 · Cited by 4
“Subsequently, several additional TBK1-phosphorylation sites on OPTN were identified by the same group [52], including S473 and S513.”
Zhu, W., Wang, X., Li, Q., Jiang, X., & Xu, G. (2026) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-026-00884-1 · Cited by 3
“TBK1 directly phosphorylates OPTN in both xenophagy and ubiquitin-independent mitophagy [138, 202].”
A cytoprotective role for optineurin during mycobacterial infection of macrophages
Ramachandran, G., Yeruva, C. V., Swarup, G., & Raghunand, T. R. (2024) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2024.101672 · Cited by 3
“Post-translational modifications such as phosphorylation of Optineurin by TBK1 regulate the autophagic activity of Opti-neurin [7,15].”
Background
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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