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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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Wu, S., Shen, Y., Zhang, S., Xiao, Y., & Shi, S. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00721 · Cited by 77
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“Phosphorylation of OPTN by TANK-binding kinase 1 (TBK1) enhances its capacity to bind to poly-Ub chains, thus creating a positive feedback cycle that promotes mitophagy [66, 67].”
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“TBK1 both associates with these Ub-binding cargo receptors and phosphorylates the Ubbinding UBAN domain in OPTN to increase the affinity of the UBAN domain for K63-linked Ub chains (9, 36).”
BackgroundResultMitophagy and DNA damage signaling in human aging
Babbar, M., Basu, S., Yang, B., Croteau, D. L., & Bohr, V. A. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111207 · Cited by 77
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Self-citationThe Multifaceted Roles of Autophagy in Flavivirus-Host Interactions
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“Notably, the TANK binding kinase 1 (TBK1)-mediated phosphorylation of p62/SQSTM1 at serine residue 403 and OPTN at serine residues 177, 473 and 513 are critical for promoting mitophagy [128] [129] [130] .”
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“Receptor proteins including optineurin, NDP52, and TAX1BP1 are recruited via their UBAN (ubiquitinbinding) motifs; the kinase TBK1 is co-recruited along with optineurin [14, 25, 34, 42, 56].”
BackgroundA Systematic Review of Suggested Molecular Strata, Biomarkers and Their Tissue Sources in ALS
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“Active TBK1 also phosphorylates optineurin at Ser473 and Ser513, stimulating the latter’s interaction with ubiquitin [63].”
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Mishra, E., & Thakur, M. K. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16062 · Cited by 73
“This facilitates a forward flow process that reinforces and strengthens the binding of OPTN to poly-Ub chains (Richter et al., 2016).”
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“TBK1 functions as an important player in inflammatory responses (11), autophagy and mitophagy (13, 14), the insulin signaling pathway (15) and innate immunity against bacterial and viral infections (16, 17).”
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“Furthermore, recent study showed that TBK1-mediated phosphorylation of autophagy adaptors generates a signal amplification loop operating in mitophagy [15].”
BackgroundMitophagy and Its Contribution to Metabolic and Aging-Associated Disorders
Liu, L., Liao, X., Wu, H., Li, Y., Zhu, Y., & Chen, Q. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.8013 · Cited by 69
“Moreover, phosphorylation of OPTN by TBK1 on S473 further enhances its binding to S65-phosphorylated ubiquitin (pS65 Ub) chains and promotes Parkin-independent mitophagy (166).”
Mechanism of Mitophagy and Its Role in Sepsis Induced Organ Dysfunction: A Review
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“In turn, TBK1 phosphorylates OPTN at S473, thereby extending the binding capacity of OPTN to diverse Ub (ubiquitin) chains (Richter et al., 2016).”
BackgroundIntegrating the UPRmtinto the mitochondrial maintenance network
Fiorese, C. J., & Haynes, C. M. (2017) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2017.1291577 · Cited by 68
“…chains and recruits the kinase TBK1 to phosphorylate the autophagy receptors, which increases the affinity of the autophagy receptor for the autophagosome component LC3 and increases autophagic clearance (Heo et al., 2015; Lazarou et al., 2015; Ordureau et al., 2015; Richter et al., 2016).”
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“(OPTN), sequestosome-1 (SQSTM1/p62), and Tax1-binding protein (TAX1BP1) [14,23,45,51-57].”
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“TBK1 and its homolog IKKε have been identified as binding partners of the autophagy receptor protein NDP52 that recognizes polyubiquitylated Salmonella enterica in human cells.”
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Optineurin provides a mitophagy contact site for TBK1 activation
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“In addition, OPTN (Ser473 and Ser513) (73, 75) and p62 (Ser403) (72) are phosphorylated by TBK1, increasing their ability to bind to UB chains, as shown in Figure 2.”
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“its kinase activity, is required for efficient xenophagy and mitophagy processes (13, 14, 18, 33, 34).”
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“Many studies have established a role for TBK-1 during mitophagy (Heo et al., 2015; Moore and Holzbaur, 2016; Richter et al., 2016) and xenophagy, the elimination of bacteria (Thurston et al.”
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“Its role in clearing damaged mitochondria is regulated through phosphorylation of OPTN by TANK-binding kinase 1 (TBK1) [163].”
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“…(Gal et al., 2009; Osaka et al., 2016), whereas Optineurin (OPTN) is an autophagy receptor, mediating the clearance of dysfunctional mitochondria through phosphorylation of another disease causing gene product, TBK-1 (Wong and Holzbaur, 2014; Moore and Holzbaur, 2016; Richter et al., 2016).”
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Novel Insights into the Anti-Aging Role of Mitophagy
(2018) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2018.05.005 · Cited by 56
PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease
Li, J., Lai, M., Zhang, X., Li, Z., Yang, D., Zhao, M., Wang, D., Sun, Z., Ehsan, S., Li, W., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04613-2 · Cited by 57
“1D and S1C) [30, 31], and LC3-II (microtubule-associated protein 1 light chain 3 beta) (Fig.”
Guo, W., Vandoorne, T., Steyaert, J., Staats, K. A., & Bosch, L. V. D. (2020) · Brain · doi:10.1093/brain/awaa022 · Cited by 58
“Besides its role in inflammation, TBK1 also plays an important role in autophagy through phosphorylation of different autophagy adaptors including p62/SQSTM1, OPTN, nuclear dot protein 52 kDa (NDP52) and Tax1 binding protein 1 (TAX1BP1) (Richter et al., 2016).”
BackgroundInfluentialNoncoding RNA MaIL1 is an integral component of the TLR4–TRIF pathway
Aznaourova, M., Janga, H., Sefried, S., Kaufmann, A. M., Dorna, J., Volkers, S. M., Georg, P., Lechner, M., Hoppe, J., Dökel, S., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920393117 · Cited by 58
“Alternatively, autophagy or mitophagy-dependent processes could mediate increased OPTN turnover in MaIL1deficient cells, as OPTN serves as an autophagy adapter, accumulating in inclusion bodies and at mitochondrial surfaces (49, 51).”
BackgroundSelective autophagy controls the stability of TBK1 via NEDD4 to balance host defense
Xie, W., Jin, S., Zhang, C., Yang, S., Wu, Y., Zhao, Y. B., Songyang, Z., & Cui, J. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00833-9 · Cited by 57
“Moreover, TBK1 promotes selective autophagy by phosphorylating cargo receptors, including OPTN, p62, NDP52 and TAX1BP1 [21].”
Background“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective
Daussy, C. F., & Wodrich, H. (2020) · Cells · doi:10.3390/cells9092042 · Cited by 52
“Some receptors including NDP52 and p62 are phosphorylated by TBK1, to enhance their ability to bind ubiquitin following recruitment to the membrane damage site [120,121].”
BackgroundRole of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases
Rienzo, M. D., Romagnoli, A., Refolo, G., Vescovo, T., Ciccosanti, F., Zuchegna, C., Lozzi, F., Occhigrossi, L., Piacentini, M., & Fimia, G. M. (2024) · Autophagy · doi:10.1080/15548627.2024.2389474 · Cited by 59
Shin, C. H., & Choi, D. (2019) · Cells · doi:10.3390/cells8020178 · Cited by 56
PTK2/FAK regulates UPS impairment via SQSTM1/p62 phosphorylation in TARDBP/TDP-43 proteinopathies
Lee, S., Jeon, Y., Cha, S. J., Kim, S., Kwon, Y., Jo, M., Jang, Y.-N., Lee, S., Kim, J., Kim, S. R., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1686729 · Cited by 59
“TBK1 phosphorylates OPTN to modulate its binding affinity for ubiquitin chains [68].”
BackgroundSelective Autophagy by Close Encounters of the Ubiquitin Kind
Vainshtein, A., & Grumati, P. (2020) · Cells · doi:10.3390/cells9112349 · Cited by 59
“The core of the LIR motif consists of a minimal consensus sequence W/F/Y-x-x-L/V/I, which is common to most cargo receptors [52], and the phosphorylation of this domain was also demonstrated to augment binding affinity to LC3 and related proteins [53].”
BackgroundInfluentialStressed mitochondria: A target to intrude alzheimer’s disease
Sharma, V., Singh, T. G., & Mehta, V. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.04.004 · Cited by 53
Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology
Valencia, M., Kim, S. R., Jang, Y., & Lee, S. H. (2021) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2021.012 · Cited by 57
“Diverse regulatory mechanisms of adaptor protein activity have been shown to enhance aggrephagy, such as phosphorylation of specific residues (Richter et al., 2016; Turco et al., 2019), oligomerization (Wurzer et al.”
BackgroundMendelian neurodegenerative disease genes involved in autophagy
Stamatakou, E., Wróbel, L., Hill, S. M., Puri, C., Son, S. M., Fujimaki, M., Zhu, Y., Siddiqi, F. H., Fernandez-Estévez, M., Manni, M. M., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-0158-y · Cited by 52
The interplay between autophagy and cGAS-STING signaling and its implications for cancer
Schmid, M., Fischer, P., Engl, M., Widder, J., Gruber, S., & Slade, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1356369 · Cited by 61
TBC1D9 regulates TBK1 activation through Ca2+ signaling in selective autophagy
Nozawa, T., Sano, S., Minowa‐Nozawa, A., Toh, H., Nakajima, S., Murase, K., Aikawa, C., & Nakagawa, I. (2020) · Nature Communications · doi:10.1038/s41467-020-14533-4 · Cited by 55
Ugbode, C., & West, R. J. H. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105144 · Cited by 55
Fu, T., Zhang, M., Zhou, Z., Wu, P., Peng, C., Wang, Y., Gong, X., Li, Y., Wang, Y., Xu, X., et al. (2021) · Science Advances · doi:10.1126/sciadv.abi6582 · Cited by 53
“(E) Combined ribbon and surface representation showing the overall architecture of NDP52(10-126)/RB1CC1(1286-1594) complex with the same color scheme and orientation as in (D).”
BackgroundMethodInfluentialA Tug of War: DNA-Sensing Antiviral Innate Immunity and Herpes Simplex Virus Type I Infection
Lin, Y., & Zheng, C. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02627 · Cited by 51
Selective Autophagy Receptors in Antiviral Defense
Viret, C., Duclaux‐Loras, R., Nancey, S., Rozières, A., & Faure, M. (2021) · Trends in Microbiology · doi:10.1016/j.tim.2021.02.006 · Cited by 50
Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies
Ma, W., Lü, Y., Jin, X., Lin, N., Zhang, L., & Song, Y. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.05.009 · Cited by 52
“In addition, autophagy receptors, such as OPTN and NDP52, can be directly recruited by PINK1 into mitochondria via ubiquitin phosphorylation, thus promoting the occurrence of mitophagy [24].”
BackgroundValionyte, E., Yang, Y., Roberts, S. L., Kelly, J., Lu, B., & Luo, S. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.11.012 · Cited by 51
Role of Autophagy Pathway in Parkinson’s Disease and Related Genetic Neurological Disorders
Themistokleous, C., Bagnoli, E., Parulekar, R., & Muqit, M. M. K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168144 · Cited by 51
Selective autophagy regulates chloroplast protein import and promotes plant stress tolerance
Chen, W., Zhang, H., Cheng, H., Sowden, R. G., Cai, W., Jarvis, P., & Ling, Q. (2023) · The EMBO Journal · doi:10.15252/embj.2022112534 · Cited by 49
“These results suggest that ubiquitin binding is also crucial for substrate recognition and physiological function of plant NBR1, similar to its mammalian homologs p62 and NBR1. p62 preferentially recognizes K63 linkages through its UBA domain (Richter et al, 2016).”
Mei, L., Chen, X., Wei, F., Huang, X. S., Liu, L., Yao, J., Chen, J., Luo, X., Wang, Z., & Yang, A. (2023) · Autophagy · doi:10.1080/15548627.2023.2234797 · Cited by 50
“In another example, PINK1 is targeted to mitochondria using rapamycin-dependent FRB-FKBP system, resulting in phosphorylation of mitochondrial ubiquitin and then recruit autophagy receptors to induce mitophagy [77].”
BackgroundCao, L., Guan, P.-P., Zhang, S.-Q., Yang, Y., Huang, X., & Wang, P. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02327-4 · Cited by 48
“Moreover, phosphorylation of OPTN by tank-binding kinase 1 (TBK1) at Ser473 enables its binding to the ubiquitin chains of pS65, which results in recruitment of OPTN to the mitochondria in PINK1-driven and parkin-independent mitophagy [80].”
BackgroundControl of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
Adriaenssens, E., Nguyen, T. N., Sawa-Makarska, J. Z., Khuu, G., Schuschnig, M., Shoebridge, S., Skulsuppaisarn, M., Watts, E. M., Csályi, K., Padman, B. S., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01338-y · Cited by 51
“TBK1 is a master kinase in mitophagy and other selective autophagy pathways, phosphorylating cargo receptors such as OPTN and NDP52 to increase their affinities for ubiquitin and LC3/GABARAP proteins [32, 33].”
Self-citationThe AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria
Malik, N., & Shaw, R. J. (2025) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120420-094431 · Cited by 57
“…aspects of mitochondrial health, such as PINK1 (Harper et al. 2018, Singh & Muqit 2020), ULK1 (Lazarou et al. 2015, Vargas et al. 2019), TBK1 (Richter et al. 2016, Vargas et al. 2019), and HRI (Chakrabarty et al. 2024, Fessler et al. 2020, Guo et al. 2020), remains a critical area for future…”
More Than Skin Deep: Autophagy Is Vital for Skin Barrier Function
Sil, P., Wong, S., & Martinez, J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01376 · Cited by 48
TAK1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform
Kehl, S. R., Soos, B. A., Saha, B., Choi, S. W., Herren, A. W., Johansen, T., & Mandell, M. A. (2019) · EMBO Reports · doi:10.15252/embr.201846238 · Cited by 49
“However, TAK1 may also affect p62 body formation through additional modifications since we found that another kinase (TBK1), known to phosphorylate p62 at both Ser-349 and Ser-403 [13,15], is dispensable for p62 body formation in response to pp242 treat-ment.”
Ye, J., Cheung, J., Gerbino, V., Ahlsén, G., Zimanyi, C. M., Hirsh, D., & Maniatis, T. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1915732116 · Cited by 49
Hegde, R. N., Chiki, A., Petricca, L., Martufi, P., Arbez, N., Mouchiroud, L., Auwerx, J. H., Landles, C., Bates, G. P., Singh‐Bains, M. K., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020104671 · Cited by 50
“To answer this question, we compared the level of phosphorylation at S13 upon coexpression of HTTex1 16Q or 72Q with wild-type TBK1 or a TBK1 kinase-dead (TBK1 KD) mutant (K38A; Richter et al , 2016).”
InfluentialGao, B., Yu, W., Lv, P., Liang, X., Sun, S., & Zhang, Y. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165997 · Cited by 48
Giovedı̀, S., Ravanelli, M. M., Parisi, B., Bettegazzi, B., & Guarnieri, F. C. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.602116 · Cited by 53
“TBK1 phosphorylates p62 and optineurin, thus increasing their ability to bind ubiquitinated proteins and enhancing the autophagic clearance of target proteins and mitochondria (Pilli et al., 2012; Matsumoto et al., 2015; Richter et al., 2016).”
BackgroundPhysiological functions of ULK1/2
Pareek, G., & Kundu, M. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168472 · Cited by 55
FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates
Schlütermann, D., Berleth, N., Deitersen, J., Hieke, N., Friesen, O., Wu, W., Stuhldreier, F., Sun, Y., Berning, L., Friedrich, A., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-92408-4 · Cited by 47
Zhang, K., Huang, Q., Li, X., Zhao, Z., Hong, C., Sun, Z., Deng, B., Li, C., Zhang, J., & Wang, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1352479 · Cited by 49
Fluorescence‐based ATG8 sensors monitor localization and function of LC3/GABARAP proteins
Stolz, A., Putyrski, M., Kutle, I., Huber, J., Wang, C., Major, V., Sidhu, S. S., Youle, R. J., Rogov, V. V., Dötsch, V., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201695063 · Cited by 47
“Analogous to ubiquitin chains and their respective receptors, phosphorylation close to the LIR motif in many cases seems to not only increase the affinity, but also broaden the selectivity of binding (Wild et al , 2011; Farre et al , 2013; Heo et al , 2015; Richter et al , 2016).”
Self-citationTRIM proteins: New players in virus-induced autophagy
Sparrer, K. M. J., & Gack, M. U. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006787 · Cited by 46
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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