Parkin is then itself phosphorylated by PINK1 fully licensing its E3 ubiquitin ligase activity to ubiquitinate numerous mitochondrial proteins with mono and short chain ubiquitin signals, the latter featuring Lys6 and Lys11 linkages [30, 31]. Parkin is activated in a stepwise fashion. Cell Rep. 2018;22:206679. 2008;28:1082534. Front Cell Neurosci. 2011;108:170049. The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, Wegener E, et al. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, et al. Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Privacy info@cshl.edu Whilst degradation of a pro-survival protein by the neuroprotective Parkin appears counter-intuitive, it might reflect a response to severe or prolonged mitochondrial damage [127]. The meeting will cover current work on the structure, regulation, and function of ubiquitin and ubiquitin-like proteins in biology. Two DUBs USP9X and USP13 deubiquitinate and stabilise MCL1, and hypomorphic mutations in both have been linked to neurodevelopmental disorders and neurodegenerative disease [128, 129]. 2015;47:e147. Compellingly, pharmacological inhibition of NLRP3 prevented -synuclein pathology and dopaminergic neurodegeneration in PD mouse models [85], hence NLRP3 inhibitors are now entering clinical trials for the treatment of PD. 2016;532:398401. Nitric Oxide (NO), reported to inhibit XIAPs ligase activity, is elevated in neurons with inflammation, and indeed, increased S-nitrosylated XIAP is found in brain tissue of patients with AD, HD and PD [113, 114], suggesting a potential role for XIAP in neurodegeneration. Although neurodegenerative diseases have long been considered neuron-autonomous disorders, an important role for non-neuronal glial cells (microglia, astrocytes, oligodendrocytes) in disease pathogenesis is emerging. 2008;19:107282. 1B) [9]. Ciechanover A. McClellan AJ, Laugesen SH, Ellgaard L. Cellular functions and molecular mechanisms of non-lysine ubiquitination. Brain. Ubiquitin and p62 at the crossroads of the UPS and autophagy Abstract To achieve homeostasis, cells evolved dynamic and self-regulating quality control processes to adapt to new environmental conditions and to prevent prolonged damage. Cell Death Differ. 2020;27:75162 e754. Article Subsequently, the Ub is transferred from the Ub~E2 conjugate to a lysine residue in a substrate either directly from the E2, mediated by a RING E3 Ub ligase, or first transferred to a HECT/RBR E3 Ub ligase before being transferred to the substrate. This conference may be supported in part byTBA. This can lead to an accumulation of defective protein aggregates, which raise the toxicity of the cell and may lead to rapid cell death (4). Glia. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Google Scholar. Nat Immunol. RIPK1, RIPK3 and MLKL are activated in the brains of AD patients and their elevated expression correlated with disease progression [137, 138]. Nature. Time will tell if the promising therapeutic opportunities, which targeting ubiquitin-dependent processes provides, will bring the desired and much needed outcomes in the form of new treatments for human diseases. 1D). Indeed, KTP treatment restored locomotor activity and aberrant mitochondrial morphology in PINK1 knockdown flies [198]. motoneurons) and complex zones for presynaptic neurotransmitter release and postsynaptic receptor regulation [12, 13]. This raises the question whether the immunoproteasome might be more effective in degrading aggregated proteins. The Atg proteins catalyse the conjugation of the lipid phosphatidylethanolamine (PE) to LC3s and mediate the expansion of the autophagophore. PubMed Central Biochim Biophys Acta Mol Basis Dis. Ugras S, Daniels MJ, Fazelinia H, Gould NS, Yocum AK, Luk KC, et al. Miller S, Muqit MMK. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr. The results revealed that J3 could inhibit mTOR, thus promoting autophagic flux and long-lived protein degradation. Dikic I. Proteasomal and autophagic degradation systems. 2019;2:125. Nat Commun. The Autophagylysosomal pathway involves ubiquitin-dependent degradation of cargo via lysosomes rather than the proteasome and is regulated by the coordinated activity of autophagy-related (Atg) genes (Fig. Internet Explorer). PubMed Hum Mol Genet. Cell. Apoptosis is largely considered a non-inflammatory mode of cell death. Thank you for visiting nature.com. DK is supported by a Fellowship from the National Health and Medical Research Council Australia. Evidence shows the regulatory role of HECT-type E3 ligases in various steps of the autophagic process. Ann Neurol. Shah and Kumar [7] review emerging regulatory principles in ubiquitin code assembly, namely the control of HECT E3 ubiquitin ligases by adaptor proteins and the regulatory effect these accessory molecules have on physiological outcomes of signalling. Annu Rev Biochem. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. Cell Death Differ. The ubiquitin-proteasome system and autophagy pathway are the two major mechanisms for maintaining this balance. In a review closely related to the theme of immune signalling, Cockram et al. Hence, USP14 knockdown enhances proteasomal degradation [167]. 2003;278:4362835. As a Ring-Between-RING E3 ligase, Parkin comprises multiple domains, including the RING1 and RING2 domains, the IBR (In-Between-RING) domain, the UPD (Unique Parkin Domain; also known as RING0) and an N-terminal ubiquitin-like (Ubl) domain [194]. Le Guerrou and Youle [17] focus on the role of ubiquitin-dependent degradation of misfolded proteins and aggregates, such as -synuclein and amyloid-, associated with neurodegenerative diseases and discuss possible reasons why the ubiquitin system fails to eliminate aggregates. One Bungtown Road, Cold Spring Harbor, NY 11724. Given the key role for ubiquitin signalling in many facets of neuronal function and survival, targeting ubiquitin signalling either to enhance the clearance of toxic protein aggregates or to rescue specific vulnerabilities as drivers of neuronal degeneration may represent game-changing treatments that slow or even stop neurodegenerative disease progression. 2018;28:70710. Gomez-Diaz C, Ikeda F. Roles of ubiquitin in autophagy and cell death. The mHTT is degraded through autophagy pathway and ubiquitin-proteasome system (UPS). Qu J, Ren X, Xue F, He Y, Zhang R, Zheng Y, et al. Nature. Neurotoxic mechanisms by which the USP14 inhibitor IU1 depletes ubiquitinated proteins and Tau in rat cerebral cortical neurons: relevance to Alzheimers disease. The tau-degrading PROTACs fused a tau-binding motif from -tubulin to peptides that bind VHL or KEAP1, adaptor proteins for Cullin E3 ligase complexes [204, 205]. Robinson EJ, Aguiar SP, Kouwenhoven WM, Starmans DS, von Oerthel L, Smidt MP, et al. To obtain 2013;49:90821. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Res. However, upon mitochondrial damage, it is instead stabilised on the outer mitochondrial membrane where it dimerises and autoactivates [28, 29]. Hum Mol Genet. Neuron. Bioorg Med Chem Lett. 1983;219:97980. Cell Chem Biol. J Neurochem. Compared to peptide PROTACs, small molecule PROTACs are likely to have better bioavailability and blood-brain barrier permeability. The NEDD4 family of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases are upregulated in AD, PD and HD, and ubiquitinate various neuronal receptors to promote their lysosomal degradation, including the dopamine transporter that mediates uptake of dopamine into dopaminergic neurons, insulin growth factor-1 receptor that is important for neurotrophic signalling, and glutamate receptors that control synapse plasticity [67, 68]. 2016;26:399422. Disrupted autophagy is observed in AD and HD [19,20,21], and mutation of various autophagy-related genes drives the pathogenesis of various neurodegenerative diseases including PD and ALS (Table1). 2002;32:4205. Sato Y, Okatsu K, Saeki Y, Yamano K, Matsuda N, Kaiho A, et al. These authors contributed equally: Marlene F Schmidt, Zhong Yan Gan, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC, 3052, Australia, Marlene F. Schmidt,Zhong Yan Gan,David Komander&Grant Dewson, Department of Medical Biology, University of Melbourne, Royal Parade, Melbourne, VIC, 3052, Australia, You can also search for this author in One Bungtown Road, Cold Spring Harbor, NY 11724 Schmidt et al. The homologous to the E6-AP carboxyl terminus (HECT)-type E3 ubiquitin ligases are the selective executers in the protein ubiquitination, playing a vital role in modulation of the protein function and stability. Neural Plast. Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C, Ramasamy K, et al. 3) [37,38,39]. 2019;13:392. [13] review the current knowledge of the function of the tumour suppressor DUB BAP1, including its roles in cell proliferation, differentiation, metabolism, and cell death, and discuss how inactivation of this DUB might cause cancer. USP14 inhibition corrects an in vivo model of impaired mitophagy. autophagy pathways by the modulation of ubiquitination dynamics. Ordureau A, Paulo JA, Zhang J, An H, Swatek KN, Cannon JR, et al. 2015;520:5537. Non-proteolytic roles of ubiquitin often involve atypical chain linkage types. This control of cell cycle re-entry is potentially dysregulated in AD, as neurons from a transgenic AD mouse model, or isolated neurons treated with A142 peptide, exhibited aberrant activation of the E3 ubiquitin ligase Itch, to provoke re-entry into the cell cycle due to Tap73 degradation, and consequently cell death [63]. 2016;22:5418. Lee BH, Lu Y, Prado MA, Shi Y, Tian G, Sun S, et al. Free Radic Biol Med. Ubiquitin ligase COP1 suppresses neuroinflammation by degrading c/EBPbeta in microglia. HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. 2016;353:6038. Although invading bacteria are known to be marked with ubiquitin and selectively targeted by xenophagy, how ubiquitin ligases recognize invading bacteria is poorly understood. Whilst an association with neurodegenerative diseasein patients has not been reported, DDB1 mutations are linked to the neurological disorder, Cockaynes syndrome, and deletion of HECTD1 or DDB1 in mice promotes neuronal degeneration and neurodevelopmental defects [54, 55]. 2020;11:578. Peptide-based PROTACs that degrade tau and -synuclein aggregates have been developed [204,205,206]. Nitrosative stress linked to sporadic Parkinsons disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. DNA adducts and oxidative base damage are observed in nuclear and mtDNA in the aging brain as well as in neurodegenerative diseases, including AD, PD and ALS [51, 52]. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. 2000;163:919. The structural and mechanistic details of Parkin activation have been resolved over the last decade [187,188,189,190,191,192,193]. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, et al. Although the myriad complexities of these linkages and their consequence are only starting to be resolved, the majority of ubiquitin signals direct tagged substrates for proteasomal degradation [5]. , Nakamura K, Matsuda N, Fischer TD, et al lens leads to p53-dependent of... ( PE ) to LC3s and mediate the expansion of the autophagic.. Mutant Huntingtin toxicity by promoting inflammation and necroptosis in ALS [ 167 ] Matsui M, Parkinson M, A..., von Oerthel L, Schlehe JS, Schlierf A, Nakahara,! 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