NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 Dec 2023
19 Dec 2023
Historique:
received:
08
02
2023
accepted:
28
11
2023
medline:
20
12
2023
pubmed:
20
12
2023
entrez:
19
12
2023
Statut:
epublish
Résumé
NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.
Identifiants
pubmed: 38114471
doi: 10.1038/s41467-023-44033-0
pii: 10.1038/s41467-023-44033-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8368Subventions
Organisme : NIA NIH HHS
ID : R01 AG065428
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Kwon, Y. T. & Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 42, 873–886 (2017).
pubmed: 28947091
doi: 10.1016/j.tibs.2017.09.002
Johnston, H. E. & Samant, R. S. Alternative systems for misfolded protein clearance: life beyond the proteasome. FEBS J. 288, 4464–4487 (2021).
pubmed: 33135311
doi: 10.1111/febs.15617
Le Guerroue, F. & Youle, R. J. Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective. Cell Death Differ. 28, 439–454 (2021).
pubmed: 33208890
doi: 10.1038/s41418-020-00667-x
Lei L., Wu Z., Winklhofer K. F. Protein quality control by the proteasome and autophagy: a regulatory role of ubiquitin and liquid-liquid phase separation. Matrix Biol. 100–101, 9–22 (2020).
Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).
pubmed: 31727826
doi: 10.1126/science.aax3769
Yin, Z., Popelka, H., Lei, Y., Yang, Y. & Klionsky, D. J. The roles of ubiquitin in mediating autophagy. Cells 9, 2025 (2020).
pubmed: 32887506
pmcid: 7564124
doi: 10.3390/cells9092025
Bauer, B., Martens, S. & Ferrari, L. Aggrephagy at a glance. J. Cell Sci. 136, jcs260888 (2023).
pubmed: 37254869
doi: 10.1242/jcs.260888
Adriaenssens, E., Ferrari, L. & Martens, S. Orchestration of selective autophagy by cargo receptors. Curr. Biol. 32, R1357–R1371 (2022).
pubmed: 36538890
doi: 10.1016/j.cub.2022.11.002
Sanchez-Martin, P. & Komatsu, M. p62/SQSTM1 - steering the cell through health and disease. J. Cell Sci. 131, jcs222836 (2018).
pubmed: 30397181
doi: 10.1242/jcs.222836
Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).
pubmed: 29618831
doi: 10.1038/s41580-018-0003-4
Vargas, J. N. S., Hamasaki, M., Kawabata, T., Youle, R. J. & Yoshimori, T. The mechanisms and roles of selective autophagy in mammals. Nat. Rev. Mol. Cell Biol. 24, 167–185 (2023).
pubmed: 36302887
doi: 10.1038/s41580-022-00542-2
Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
pubmed: 16286508
pmcid: 2171557
doi: 10.1083/jcb.200507002
Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009).
pubmed: 19250911
doi: 10.1016/j.molcel.2009.01.020
Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 28, 405–415 (2018).
pubmed: 29507397
pmcid: 5939046
doi: 10.1038/s41422-018-0017-7
Zaffagnini, G. et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308 (2018).
pubmed: 29343546
pmcid: 5830917
doi: 10.15252/embj.201798308
Turco, E. et al. Reconstitution defines the roles of p62, NBR1, and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat. Commun. 12, 5212 (2021).
pubmed: 34471133
pmcid: 8410870
doi: 10.1038/s41467-021-25572-w
Ohnstad, A. E. et al. Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. EMBO J. 39, e104948 (2020).
pubmed: 33226137
pmcid: 7737610
doi: 10.15252/embj.2020104948
Sarraf, S. A. et al. Loss of TAX1BP1-directed autophagy results in protein aggregate accumulation in the brain. Mol. Cell 80, 779–795 e710 (2020).
pubmed: 33207181
pmcid: 7771836
doi: 10.1016/j.molcel.2020.10.041
Swatek, K. N. & Komander, D. Ubiquitin modifications. Cell Res. 26, 399–422 (2016).
pubmed: 27012465
pmcid: 4822133
doi: 10.1038/cr.2016.39
Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016).
pubmed: 27230526
doi: 10.1038/ncb3358
Oh, E., Akopian, D. & Rape, M. Principles of ubiquitin-dependent signaling. Annu Rev. Cell Dev. Biol. 34, 137–162 (2018).
pubmed: 30110556
doi: 10.1146/annurev-cellbio-100617-062802
Dikic I., Schulman B. A. An expanded lexicon for the ubiquitin code. Nat. Rev. Mol. Cell Biol. 24, 1−15 (2022).
Kirisako, T. et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 25, 4877–4887 (2006).
pubmed: 17006537
pmcid: 1618115
doi: 10.1038/sj.emboj.7601360
Iwai, K. Discovery of linear ubiquitination, a crucial regulator for immune signaling and cell death. FEBS J. 288, 1060–1069 (2021).
pubmed: 32627388
doi: 10.1111/febs.15471
Fiil, B. K. & Gyrd-Hansen, M. The Met1-linked ubiquitin machinery in inflammation and infection. Cell Death Differ. 28, 557–569 (2021).
pubmed: 33473179
pmcid: 7816137
doi: 10.1038/s41418-020-00702-x
Fuseya, Y. & Iwai, K. Biochemistry, pathophysiology, and regulation of linear ubiquitination: intricate regulation by coordinated functions of the associated ligase and deubiquitinase. Cells 10, 2706 (2021).
pubmed: 34685685
pmcid: 8534859
doi: 10.3390/cells10102706
Jahan, A. S., Elbaek, C. R. & Damgaard, R. B. Met1-linked ubiquitin signalling in health and disease: inflammation, immunity, cancer, and beyond. Cell Death Differ. 28, 473–492 (2021).
pubmed: 33441937
pmcid: 7862443
doi: 10.1038/s41418-020-00676-w
Oikawa, D., Sato, Y., Ito, H. & Tokunaga, F. Linear ubiquitin code: its writer, erasers, decoders, inhibitors, and implications in disorders. Int J. Mol. Sci. 21, 3381 (2020).
pubmed: 32403254
pmcid: 7246992
doi: 10.3390/ijms21093381
Dittmar, G. & Winklhofer, K. F. Linear ubiquitin chains: cellular functions and strategies for detection and quantification. Front. Chem. 7, 915 (2019).
pubmed: 31998699
doi: 10.3389/fchem.2019.00915
Rittinger, K. & Ikeda, F. Linear ubiquitin chains: enzymes, mechanisms and biology. Open Biol. 7, 170026 (2017).
pubmed: 28446710
pmcid: 5413910
doi: 10.1098/rsob.170026
Hrdinka, M. & Gyrd-Hansen, M. The Met1-linked ubiquitin machinery: emerging themes of (De)regulation. Mol. Cell 68, 265–280 (2017).
pubmed: 29053955
doi: 10.1016/j.molcel.2017.09.001
Tokunaga, F. & Ikeda, F. Linear ubiquitination in immune and neurodegenerative diseases, and beyond. Biochem. Soc. Trans. 50, 799–811 (2022).
pubmed: 35343567
doi: 10.1042/BST20211078
Shibata, Y. & Komander, D. Lubac. Curr. Biol. 32, R506–R508 (2022).
pubmed: 35671719
doi: 10.1016/j.cub.2022.04.041
Spit, M., Rieser, E. & Walczak, H. Linear ubiquitination at a glance. J. Cell Sci. 132, jcs208512 (2019).
pubmed: 30659056
doi: 10.1242/jcs.208512
Zinngrebe, J. & Walczak, H. TLRs go linear - on the ubiquitin edge. Trends Mol. Med. 23, 296–309 (2017).
pubmed: 28325627
doi: 10.1016/j.molmed.2017.02.003
Sasaki, K. & Iwai, K. Roles of linear ubiquitinylation, a crucial regulator of NF-kappaB and cell death, in the immune system. Immunol. Rev. 266, 175–189 (2015).
pubmed: 26085215
doi: 10.1111/imr.12308
Ikeda, F. Linear ubiquitination signals in adaptive immune responses. Immunol. Rev. 266, 222–236 (2015).
pubmed: 26085218
pmcid: 4506786
doi: 10.1111/imr.12300
Iwai, K., Fujita, H. & Sasaki, Y. Linear ubiquitin chains: NF-kappaB signalling, cell death and beyond. Nat. Rev. Mol. Cell Biol. 15, 503–508 (2014).
pubmed: 25027653
doi: 10.1038/nrm3836
Maubach, G., Schmadicke, A. C. & Naumann, M. NEMO links nuclear factor-kappaB to human diseases. Trends Mol. Med. 23, 1138–1155 (2017).
pubmed: 29128367
doi: 10.1016/j.molmed.2017.10.004
Clark, K., Nanda, S. & Cohen, P. Molecular control of the NEMO family of ubiquitin-binding proteins. Nat. Rev. Cancer 13, 673–685 (2013).
Israel, A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb. Perspect. Biol. 2, a000158 (2010).
pubmed: 20300203
pmcid: 2829958
doi: 10.1101/cshperspect.a000158
Annibaldi, A. & Meier, P. Checkpoints in TNF-induced cell death: implications in inflammation and cancer. Trends Mol. Med. 24, 49–65 (2018).
pubmed: 29217118
doi: 10.1016/j.molmed.2017.11.002
Brenner, D., Blaser, H. & Mak, T. W. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol. 15, 362–374 (2015).
pubmed: 26008591
doi: 10.1038/nri3834
Smahi, A. et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405, 466–472 (2000).
pubmed: 10839543
doi: 10.1038/35013114
Fusco, F. et al. EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-kappaB pathway can cause immunodeficiency and/or inflammation. Int. Rev. Immunol. 34, 445–459 (2015).
pubmed: 26269396
doi: 10.3109/08830185.2015.1055331
Conte, M. I. et al. Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Hum. Mutat. 35, 165–177 (2014).
pubmed: 24339369
doi: 10.1002/humu.22483
Narayanan, M. J., Rangasamy, S. & Narayanan, V. Incontinentia pigmenti (Bloch-Sulzberger syndrome). Handb. Clin. Neurol. 132, 271–280 (2015).
pubmed: 26564087
doi: 10.1016/B978-0-444-62702-5.00020-2
Cammarata-Scalisi, F., Fusco, F. & Ursini, M. V. Incontinentia Pigmenti. Actas Dermosifiliogr. 110, 273–278 (2019).
pubmed: 30660327
doi: 10.1016/j.ad.2018.10.004
van Well, E. M. et al. A protein quality control pathway regulated by linear ubiquitination. EMBO J. 38, e100730 (2019).
pubmed: 30886048
pmcid: 6484417
doi: 10.15252/embj.2018100730
Goel, S. et al. Linear ubiquitination induces NEMO phase separation to activate NF-kappaB signaling. Life Sci. Alliance 6, e202201607 (2023).
pubmed: 36720498
pmcid: 9889916
doi: 10.26508/lsa.202201607
Gupta, R. et al. Firefly luciferase mutants as sensors of proteome stress. Nat. Methods 8, 879–884 (2011).
pubmed: 21892152
doi: 10.1038/nmeth.1697
Blumenstock, S. et al. Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease. EMBO J. 40, e107260 (2021).
pubmed: 34410010
pmcid: 8488555
doi: 10.15252/embj.2020107260
Polinski, N. K. et al. Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson’s Disease in Rodents. J. Parkinsons Dis. 8, 303–322 (2018).
pubmed: 29400668
pmcid: 6004926
doi: 10.3233/JPD-171248
Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).
pubmed: 25122523
pmcid: 4372899
doi: 10.1038/nprot.2014.143
Trinkaus, V. A. et al. In situ architecture of neuronal alpha-Synuclein inclusions. Nat. Commun. 12, 2110 (2021).
pubmed: 33854052
pmcid: 8046968
doi: 10.1038/s41467-021-22108-0
Matsumoto, M. L. et al. Engineering and structural characterization of a linear polyubiquitin-specific antibody. J. Mol. Biol. 418, 134–144 (2012).
pubmed: 22227388
doi: 10.1016/j.jmb.2011.12.053
Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat. Cell Biol. 11, 123–132 (2009).
pubmed: 19136968
doi: 10.1038/ncb1821
Fujita, H. et al. Mechanism underlying IkappaB kinase activation mediated by the linear ubiquitin chain assembly complex. Mol. Cell Biol. 34, 1322–1335 (2014).
pubmed: 24469399
pmcid: 3993567
doi: 10.1128/MCB.01538-13
Rahighi, S., Iyer, M., Oveisi, H., Nasser, S. & Duong, V. Structural basis for the simultaneous recognition of NEMO and acceptor ubiquitin by the HOIP NZF1 domain. Sci. Rep. 12, 12241 (2022).
pubmed: 35851409
pmcid: 9294000
doi: 10.1038/s41598-022-16193-4
Hubeau, M. et al. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein. Blood 118, 926–935 (2011).
pubmed: 21622647
pmcid: 3251327
doi: 10.1182/blood-2010-10-315234
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 136, 1098–1109 (2009).
pubmed: 19303852
doi: 10.1016/j.cell.2009.03.007
Noad, J., von der Malsburg, A., Pathe, C., Michel, M. A., Komander, D. & Randow, F. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-kappaB. Nat. Microbiol. 2, 17063 (2017).
pubmed: 28481331
pmcid: 5576533
doi: 10.1038/nmicrobiol.2017.63
van Wijk, S. J. L. et al. Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-kappaB and restricts bacterial proliferation. Nat. Microbiol 2, 17066 (2017).
pubmed: 28481361
doi: 10.1038/nmicrobiol.2017.66
Otten, E. G. et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 594, 111–116 (2021).
pubmed: 34012115
pmcid: 7610904
doi: 10.1038/s41586-021-03566-4
Stefanis, L., Emmanouilidou, E., Pantazopoulou, M., Kirik, D., Vekrellis, K. & Tofaris, G. K. How is alpha-synuclein cleared from the cell? J. Neurochem. 150, 577–590 (2019).
pubmed: 31069800
doi: 10.1111/jnc.14704
Sahoo, S., Padhy, A. A., Kumari, V. & Mishra, P. Role of ubiquitin-proteasome and autophagy-lysosome pathways in alpha-synuclein aggregate clearance. Mol. Neurobiol. 59, 5379–5407 (2022).
pubmed: 35699874
doi: 10.1007/s12035-022-02897-1
Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38–48 (2013).
pubmed: 23254192
pmcid: 4295774
doi: 10.1038/nrn3406
Lamark, T., Svenning, S. & Johansen, T. Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem. 61, 609–624 (2017).
pubmed: 29233872
doi: 10.1042/EBC20170035
Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).
pubmed: 17580304
doi: 10.1074/jbc.M702824200
Danieli, A. & Martens, S. p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy. J. Cell Sci. 131, jcs214304 (2018).
pubmed: 30287680
doi: 10.1242/jcs.214304
Wurzer, B. et al. Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. eLife 4, e08941 (2015).
pubmed: 26413874
pmcid: 4684078
doi: 10.7554/eLife.08941
Zotti, T. et al. TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1. Mol. Immunol. 58, 27–31 (2014).
pubmed: 24270048
pmcid: 3909464
doi: 10.1016/j.molimm.2013.10.015
Martin, P., Diaz-Meco, M. T. & Moscat, J. The signaling adapter p62 is an important mediator of T helper 2 cell function and allergic airway inflammation. EMBO J. 25, 3524–3533 (2006).
pubmed: 16874300
pmcid: 1538553
doi: 10.1038/sj.emboj.7601250
Harding, O., Holzer, E., Riley, J. F., Martens, S. & Holzbaur, E. L. F. Damaged mitochondria recruit the effector NEMO to activate NF-kappaB signaling. Mol. Cell 83, 3188–3204 e3187 (2023).
pubmed: 37683611
doi: 10.1016/j.molcel.2023.08.005
Kuusisto, E., Salminen, A. & Alafuzoff, I. Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12, 2085–2090 (2001).
pubmed: 11447312
doi: 10.1097/00001756-200107200-00009
Trejo-Lopez, J. A. et al. Generation and characterization of novel monoclonal antibodies targeting p62/sequestosome-1 across human neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 79, 407–418 (2020).
pubmed: 32106300
pmcid: 7092360
doi: 10.1093/jnen/nlaa007
Turco, E. et al. FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Mol. Cell 74, 330–346 e311 (2019).
pubmed: 30853400
pmcid: 6477179
doi: 10.1016/j.molcel.2019.01.035
Jakobi, A. J. et al. Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake. Nat. Commun. 11, 440 (2020).
pubmed: 31974402
pmcid: 6978347
doi: 10.1038/s41467-020-14343-8
Du, M., Ea, C. K., Fang, Y. & Chen, Z. J. Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-kappaB. Mol. Cell 82, 2415–2426.e5 (2022).
pubmed: 35477005
pmcid: 9402427
doi: 10.1016/j.molcel.2022.03.037
Emmerich, C. H. et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc. Natl Acad. Sci. USA 110, 15247–15252 (2013).
pubmed: 23986494
pmcid: 3780889
doi: 10.1073/pnas.1314715110
Yamasaki, A. et al. Liquidity Is a Critical Determinant for Selective Autophagy of Protein Condensates. Mol. Cell 77, 1163–1175 e1169 (2020).
pubmed: 31995729
doi: 10.1016/j.molcel.2019.12.026
Gallagher, E. R. & Holzbaur, E. L. F. The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy. Cell Rep. 42, 112037 (2023).
pubmed: 36701233
pmcid: 10366342
doi: 10.1016/j.celrep.2023.112037
Ma, X., Zhang, M. & Ge, L. A switch of chaperonin function regulates the clearance of solid protein aggregates. Autophagy 18, 2746–2748 (2022).
pubmed: 35380909
pmcid: 9629062
doi: 10.1080/15548627.2022.2052581
Peng, S. Z. et al. Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates. Nat. Commun. 12, 5989 (2021).
pubmed: 34645818
pmcid: 8514450
doi: 10.1038/s41467-021-26295-8
Kageyama, S. et al. p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response. Nat. Commun. 12, 16 (2021).
pubmed: 33397898
pmcid: 7782522
doi: 10.1038/s41467-020-20185-1
Komander, D., Reyes-Turcu, F., Licchesi, J. D., Odenwaelder, P., Wilkinson, K. D. & Barford, D. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 10, 466–473 (2009).
pubmed: 19373254
pmcid: 2680876
doi: 10.1038/embor.2009.55
Wagner, S. et al. Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins. Oncogene 27, 3739–3745 (2008).
pubmed: 18212736
doi: 10.1038/sj.onc.1211042
Lo, Y. C. et al. Structural basis for recognition of diubiquitins by NEMO. Mol. Cell 33, 602–615 (2009).
pubmed: 19185524
pmcid: 2749619
doi: 10.1016/j.molcel.2009.01.012
Laplantine, E. et al. NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain. EMBO J. 28, 2885–2895 (2009).
pubmed: 19763089
pmcid: 2760117
doi: 10.1038/emboj.2009.241
Cordier, F., Grubisha, O., Traincard, F., Veron, M., Delepierre, M. & Agou, F. The zinc finger of NEMO is a functional ubiquitin-binding domain. J. Biol. Chem. 284, 2902–2907 (2009).
pubmed: 19033441
doi: 10.1074/jbc.M806655200
Schrofelbauer, B., Polley, S., Behar, M., Ghosh, G. & Hoffmann, A. NEMO ensures signaling specificity of the pleiotropic IKKbeta by directing its kinase activity toward IkappaBalpha. Mol. Cell 47, 111–121 (2012).
pubmed: 22633953
pmcid: 3398199
doi: 10.1016/j.molcel.2012.04.020
Zilberman-Rudenko, J. et al. Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-kappaB activation and autoinflammatory disease. Proc. Natl Acad. Sci. USA 113, 1612–1617 (2016).
pubmed: 26802121
pmcid: 4760784
doi: 10.1073/pnas.1518163113
Herhaus, L. et al. Molecular recognition of M1-linked ubiquitin chains by native and phosphorylated UBAN domains. J. Mol. Biol. 431, 3146–3156 (2019).
pubmed: 31247202
doi: 10.1016/j.jmb.2019.06.012
Merline, R. et al. A20 binding and inhibitor of nuclear factor kappa B (NF-kappaB)-1 (ABIN-1): a novel modulator of mitochondrial autophagy. Am. J. Physiol. Cell Physiol. 324, C339–C352 (2023).
pubmed: 36440857
doi: 10.1152/ajpcell.00493.2022
Tusco, R. et al. Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses. Nat. Commun. 8, 1264 (2017).
pubmed: 29097655
pmcid: 5668318
doi: 10.1038/s41467-017-01287-9
Wu, Z. et al. LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-kappaB to the nucleus. EMBO J. 41, e112006 (2022).
pubmed: 36398858
pmcid: 9753471
doi: 10.15252/embj.2022112006
Jain, A. et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285, 22576–22591 (2010).
pubmed: 20452972
pmcid: 2903417
doi: 10.1074/jbc.M110.118976
Meffert, M. K., Chang, J. M., Wiltgen, B. J., Fanselow, M. S., Baltimore, D. & NF-kappa, B. functions in synaptic signaling and behavior. Nat. Neurosci. 6, 1072–1078 (2003).
pubmed: 12947408
doi: 10.1038/nn1110
Neidl, R. et al. Late-life environmental enrichment induces acetylation events and nuclear factor kappab-dependent regulations in the hippocampus of aged rats showing improved plasticity and learning. J. Neurosci. 36, 4351–4361 (2016).
pubmed: 27076430
pmcid: 6601779
doi: 10.1523/JNEUROSCI.3239-15.2016
O’Riordan, K. J. et al. Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors. J. Neurosci. 26, 4870–4879 (2006).
pubmed: 16672661
pmcid: 6674168
doi: 10.1523/JNEUROSCI.4527-05.2006
Dresselhaus, E. C., Boersma, M. C. H. & Meffert, M. K. Targeting of NF-kappaB to dendritic spines is required for synaptic signaling and spine development. J. Neurosci. 38, 4093–4103 (2018).
pubmed: 29555853
pmcid: 5963848
doi: 10.1523/JNEUROSCI.2663-16.2018
Bhakar, A. L. et al. Constitutive nuclear factor-kappa B activity is required for central neuron survival. J. Neurosci. 22, 8466–8475 (2002).
pubmed: 12351721
pmcid: 6757785
doi: 10.1523/JNEUROSCI.22-19-08466.2002
Blondeau, N., Widmann, C., Lazdunski, M. & Heurteaux, C. Activation of the nuclear factor-kappaB is a key event in brain tolerance. J. Neurosci. 21, 4668–4677 (2001).
pubmed: 11425894
pmcid: 6762345
doi: 10.1523/JNEUROSCI.21-13-04668.2001
Cheng, B., Christakos, S. & Mattson, M. P. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 (1994).
pubmed: 7507336
doi: 10.1016/0896-6273(94)90159-7
Turrin, N. P. & Rivest, S. Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J. Neurosci. 26, 143–151 (2006).
pubmed: 16399681
pmcid: 6674332
doi: 10.1523/JNEUROSCI.4032-05.2006
Carter, B. D. et al. Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272, 542–545 (1996).
pubmed: 8614802
doi: 10.1126/science.272.5261.542
Foehr, E. D., Lin, X., O’Mahony, A., Geleziunas, R., Bradshaw, R. A., Greene, W. C. & NF-kappa, B. signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. J. Neurosci. 20, 7556–7563 (2000).
pubmed: 11027214
pmcid: 6772878
doi: 10.1523/JNEUROSCI.20-20-07556.2000
Nakajima, K. et al. Neurotrophins regulate the function of cultured microglia. Glia 24, 272–289 (1998).
pubmed: 9775979
doi: 10.1002/(SICI)1098-1136(199811)24:3<272::AID-GLIA2>3.0.CO;2-4
Hayashi, H. et al. Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene 19, 4469–4475 (2000).
pubmed: 11002419
doi: 10.1038/sj.onc.1203799
Meka, D. P. et al. Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. J. Clin. Invest. 125, 1873–1885 (2015).
pubmed: 25822020
pmcid: 4611569
doi: 10.1172/JCI79300
Muller-Rischart, A. K. et al. The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Mol. Cell 49, 908–921 (2013).
pubmed: 23453807
doi: 10.1016/j.molcel.2013.01.036
Henn, I. H. et al. Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J. Neurosci. 27, 1868–1878 (2007).
pubmed: 17314283
pmcid: 6673568
doi: 10.1523/JNEUROSCI.5537-06.2007
Ayaki, T. et al. Multiple proteinopathies in familial ALS cases with optineurin mutations. J. Neuropathol. Exp. Neurol. 77, 128–138 (2018).
pubmed: 29272468
doi: 10.1093/jnen/nlx109
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
pubmed: 25741868
pmcid: 4544753
doi: 10.1038/gim.2015.30
Schmidt-Supprian, M. et al. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981–992 (2000).
pubmed: 10911992
doi: 10.1016/S1097-2765(00)80263-4
Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).
pubmed: 18083104
doi: 10.1016/j.cell.2007.10.035