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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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Self-citationMechanisms Associated with Mitophagy and Ferroptosis in Cerebral Ischemia-reperfusion Injury
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Protein misfolding and mitochondrial dysfunction in glaucoma
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“PINK1-deficiency has been shown to impair the phosphorylation and activation of TBK1, which mediates numerous downstream pathways, including proteophagy and innate immunity (Shu et al., 2013;Lazarou et al., 2015;Richter et al., 2016).”
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Pied, N., Daussy, C. F., Denis, Z., Ragues, J., Faure, M., Iggo, R. D., Tschan, M. P., Roger, B., Rayne, F., & Wodrich, H. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010736 · Cited by 24
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“It selectively abolishes the binding of the TBK1 protein to the autophagy adaptor protein optineurin (Freischmidt et al., 2015; Pottier et al., 2015; Richter et al., 2016; Li et al., 2016; Moore and Holzbaur, 2016).”
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“OPTN activity is regulated by TBK1, which phosphorylates OPTN at S177, in turn enhancing the binding of the protein to ubiquitinated substrates and promoting its translocation in damaged mitochondria [64,66].”
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“TBK1 contributes to the elimination of such damaged mitochondria via selective autophagy, called mitophagy, by phosphorylating optineurin (21) or Rab7A (22).”
BackgroundMechanisms of neurodegeneration in Parkinson’s disease: keep neurons in the PINK1
Brunelli, F., Valente, E. M., & Arena, G. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111277 · Cited by 22
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“It also has a major role in autophagy [31], and there is colocalization between TBK1 and autophagic cargo adaptors, including p62 [32] and optineurin [33].”
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“The phosphorylation of OPTN enhances the efficiency of selective autophagy (Richter et al., 2016).”
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“TBK1 is a regulator of autophagy and mitophagy via the phosphorylation of the autophagy cargo receptors SQSTM1/p62 (hereafter p62), and OPTN [29, 30].”
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“TBK1 belongs to a serine/threonine protein kinase of the IKK kinase family, and functions as an essential player in autophagy and mitophagy (4, 5), the insulin signaling pathway (6), and innate inflammatory responses (7, 8).”
BackgroundMaculins, T., Verschueren, E., Hinkle, T. B., Choi, M., Chang, P., Chalouni, C. M., Rao, S. C., Kwon, Y. C., Lim, J., Katakam, A. K., et al. (2021) · eLife · doi:10.7554/elife.62320 · Cited by 16
“Previous work from several groups have demonstrated that TBK1 regulates OPTN and SQSTM through phosphorylation, although the sites quantified in this dataset differ from those previously characterized in detail (Heo et al., 2015; Matsumoto et al., 2015; Richter et al., 2016).”
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“Protein (organism) Sub-organellar Localization Inducing signal(s) Modification Reference autophagy receptors driven mitophagy Atg32 (yeast) OMM Stationary phase or upon nitrogen starvation Phosphorylation (Kanki et al., 2009; Okamoto et al., 2009; Kanki et al., 2013; Furukawa et al., 2018) BCL2L13 (mammal) OMM Unknown…”
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The compartmentalised nature of neuronal mitophagy: molecular insights and implications
Borbolis, F., & Palikaras, K. (2022) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2022.31 · Cited by 16
ATG4B antagonizes antiviral immunity by GABARAP-directed autophagic degradation of TBK1
Xie, W., Zhang, C., Wang, Z., Chen, H., Gu, T., Zhou, T., Wu, Y., Xia, F., Li, M., Wang, J., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2233846 · Cited by 16
“Interestingly, TBK1 has been reported to regulate autophagy process by targeting various proteins, such as STX17 (syntaxin 17) and cargo receptors (SQSTM1/p62, OPTN, CALCOCO2/NDP52 and TAX1BP1) [34,35].”
Common Traits Spark the Mitophagy/Xenophagy Interplay
Singh, A., Kendall, S. L., & Campanella, M. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01172 · Cited by 17
“In 2016, Dikic and colleagues showed that TBK1 integrates the ubiquitin dependent signaling events in Mitophagy upstream of the process (Heo et al., 2015; Moore and Holzbaur, 2016; Richter et al., 2016).”
BackgroundLiu, J., Zhang, M., & Qu, Y.-Q. (2020) · International Journal of COPD · doi:10.2147/copd.s265728 · Cited by 18
What We Learned From Big Data for Autophagy Research
Jacomin, A., Gul, L., Sudhakar, P., Korcsmaros, T. D., & Nezis, I. P. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00092 · Cited by 16
“As such, autophagy facilitates the disposal of supernumerary or damaged proteins and organelles before they become toxic to the cell (Pankiv et al., 2007; Kirkin et al., 2009; Okamoto et al., 2009; Richter et al., 2016).”
BackgroundBeckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 19
TBK1 haploinsufficiency in ALS and FTD compromises membrane trafficking
Lu, Y., Almeida, S., & Gao, F. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02331-1 · Cited by 15
“In particular, TBK1 phosphorylates several autophagy adaptor proteins, including SQSTM1/p62, optineurin, and NDP52 [6, 10, 11, 15].”
BackgroundPatil, C. D., Suryawanshi, R. K., Ames, J. M., Koganti, R., Agelidis, A. M., Kapoor, D., Yadavalli, T., Koujah, L., Tseng, H. C., & Shukla, D. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100472 · Cited by 15
Mechanistic insights into the interactions of TAX1BP1 with RB1CC1 and mammalian ATG8 family proteins
Zhang, M., Wang, Y., Gong, X., Wang, Y., Zhang, Y., Tang, Y., Zhou, X., Liu, H., Huang, Y., Zhang, J., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315550121 · Cited by 17
“The associations between autophagy receptors and TBK1 as well as the activation of the kinase activity of TBK1 were well demonstrated to play critical roles in promoting different forms of selective autophagy mediated by p62, Optineurin, and NDP52 (17, 32, 37–40, 50, 57).”
The Autophagy Receptor TAX1BP1 (T6BP) improves antigen presentation by MHC‐II molecules
Pereira, M., Richetta, C., Sarango, G., Kumari, A., Ghosh, M., Bertrand, L., Pionneau, C., Gall, M. L., Grégoire, S., Jeger‐Madiot, R., et al. (2022) · EMBO Reports · doi:10.15252/embr.202255470 · Cited by 16
Rab-dependent cellular trafficking and amyotrophic lateral sclerosis
Parakh, S., Perri, E. R., Jagaraj, C. J., Ragagnin, A., & Atkin, J. D. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1553926 · Cited by 15
“Similarly, in ALS, mutant optineurin is not phosphorylated by TBK1, leading to defective mitophagy (Duan et al. 2010; Hong et al. 2012; Richter et al. 2016).”
BackgroundMitophagy: A double-edged sword in tumor cell death regulation and therapeutic response
Chu, T., Huang, Z., & Ma, W. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152254 · Cited by 14
Receptor-mediated mitophagy: a new target of neurodegenerative diseases
Yang, J., Yang, F., Chen, G., Liu, M., Yuan, S., & Zhang, T. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1665315 · Cited by 16
Core principles of autophagy initiation mechanisms
Kotani, T., & Nakatogawa, H. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01752-4 · Cited by 15
Alternative pathways driven by STING: From innate immunity to lipid metabolism
Vila, I. K., Guha, S., Kalucka, J. M., Olagnier, D. P., & Laguette, N. (2022) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2022.08.006 · Cited by 15
Manipulating autophagic degradation in human diseases: from mechanisms to interventions
Zhang, Y., Liu, X., Klionsky, D. J., Lu, B., & Zhong, Q. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac043 · Cited by 14
“Cargo recruitment of the ULK1 complex can be positively regulated by TBK1 (TANK binding kinase 1), a Ser/Thr kinase that can be recruited by cargo receptors including NDP52 [91, 112, 219], TAX1BP1 [220], and OPTN [219, 221].”
The ULK complex–LRRK1 axis regulates Parkin-mediated mitophagy via Rab7 Ser-72 phosphorylation
Fujita, K., Kedashiro, S., Yagi, T., Hisamoto, N., Matsumoto, K., & Hanafusa, H. (2022) · Journal of Cell Science · doi:10.1242/jcs.260395 · Cited by 16
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“Specifically, Tank-binding kinase 1 (TBK1) can phosphorylate NDP52 and OPTN to enhance their activity (Richter et al., 2016), which is activated by the PINK1-parkin pathway after mitochondrial damage, which is also a feedforward mechanism (Heo et al.”
BackgroundWen, D., Ji, Y., Li, Y., Duan, W., Wang, Y., Li, Z., Tao, M., & Liu, Y. (2023) · FEBS Journal · doi:10.1111/febs.17009 · Cited by 18
“OPTN recruits TBK-1 to damaged mitochondria, and OPTN is phosphorylated by TBK-1 and then combines with LC3 to promote mito-phagy [50].”
BackgroundThe critical roles of STING in mitochondrial homeostasis
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Interplay between group A Streptococcus and host innate immune responses
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“…nuclear dot protein 52 kDa (NDP52), and optineurin, which are further phosphorylated via TANK-binding kinase 1 (TBK1) or other kinases, to facilitate LC3 interaction with the LC3-interacting region of autophagy receptors for phagophore recruitment and autophagosome formation (246, 247, 252–255).”
BackgroundKulkarni, P. G., Mohire, V. M., Waghmare, P. P., & Banerjee, T. (2024) · Mitochondrion · doi:10.1016/j.mito.2024.101874 · Cited by 16
Organellophagy regulates cell death:A potential therapeutic target for inflammatory diseases
Duan, Y., Yao, R.-Q., Ling, H., Zheng, L., Fan, Q. W., Li, Q., Wang, L., Zhou, Q.-Y., Wu, L.-M., Dai, X., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.05.012 · Cited by 16
“…proteins, such as opti-neurin (OPTN) and nuclear dot protein 52 (NDP52), recognize and bind to the phospho-ubiquitinated outer mitochondrial membrane (OMM) proteins through their ubiquitin-binding domain and subsequently interact with MAP1LC3 via LIR to initiate autophago-some formation [18,19].”
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Identification of a splice variant of optineurin which is defective in autophagy and phosphorylation
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“TBK1 phosphorylates a selective autophagy receptor, OPTN, at Ser177, that enhances interaction with ubiquitinated cargoes and is an autophagy modifier of the LC3 family [23].”
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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