Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

Cell Death and Differentiation, Год журнала: 2021, Номер 28(2), С. 570 - 590

Опубликована: Янв. 7, 2021

Abstract Neurodegenerative diseases are characterised by progressive damage to the nervous system including selective loss of vulnerable populations neurons leading motor symptoms and cognitive decline. Despite millions people being affected worldwide, there still no drugs that block neurodegenerative process stop or slow disease progression. Neuronal death in these is often linked misfolded proteins aggregate within brain (proteinopathies) as a result disease-related gene mutations abnormal protein homoeostasis. There two major degradation pathways rid cell unwanted prevent their accumulation maintain health cell: ubiquitin–proteasome autophagy–lysosomal pathway. Both degradative depend on modification targets with ubiquitin. Aging primary risk factor most Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis. With aging general reduction proteasomal autophagy, consequent increase potentially neurotoxic aggregates β-amyloid, tau, α-synuclein, SOD1 TDP-43. An over-looked yet component ubiquitin, implicating either an adaptive response toxic evidence dysregulated ubiquitin-mediated driving aggregation. In addition, non-degradative ubiquitin signalling critical for homoeostatic mechanisms fundamental neuronal function survival, mitochondrial homoeostasis, receptor trafficking DNA responses, whilst also playing role inflammatory processes. This review will discuss current understanding ubiquitin-dependent processes emergence target development much needed new treat disease.

Язык: Английский

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An expanded lexicon for the ubiquitin code

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 24(4), С. 273 - 287

Опубликована: Окт. 25, 2022

Язык: Английский

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Beyond K48 and K63: non-canonical protein ubiquitination

Cellular & Molecular Biology Letters, Год журнала: 2021, Номер 26(1)

Опубликована: Янв. 5, 2021

Protein ubiquitination has become one of the most extensively studied post-translational modifications. Originally discovered as a critical element in highly regulated proteolysis, is now regarded essential for many other cellular processes. This results from unique features ubiquitin (Ub) and its ability to form various homo- heterotypic linkage types involving seven different lysine residues or free amino group located at N-terminus. While K48- K63-linked chains are broadly covered literature, assembled through K6, K11, K27, K29, K33 deserve equal attention light latest discoveries. Here, we provide concise summary recent advances field these poorly understood Ub linkages their possible roles vivo.

Язык: Английский

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Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

Journal of Biological Chemistry, Год журнала: 2021, Номер 297(3), С. 101077 - 101077

Опубликована: Авг. 12, 2021

Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced conjugases ligases removing from these substrates. Many DUBs selectively physiological pathways employing conserved mechanisms of bond cleavage. DUB activity highly regulated environments through protein–protein interaction, posttranslational modification, relocalization. The largest family DUBs, cysteine proteases, also sensitive regulation oxidative stress, as reactive oxygen species (ROS) directly modify catalytic required for their enzymatic activity. Current research has implicated human diseases, including various cancers neurodegenerative disorders. Due selectivity functional roles, have become important targets therapeutic development treat conditions. This review will discuss main classes regulatory with particular focus on redox its during stress. When subject ubiquitination arises, most people think canonical pathway ubiquitin-dependent proteasomal targeting. This, however, only represents fraction diversity ubiquitin. small (76 amino acid) eukaryotic that acts modifier (1Watson D.C. Levy W.B. Dixon G.H. Free non-histone trout testis chromatin.Nature. 1978; 276: 196-198Crossref PubMed Google Scholar). very robust diverse where series act coordinated covalently one more molecules form chain (2Komander D. Rape M. code.Annu. Rev. Biochem. 2012; 81: 203-229Crossref Scopus (1845) Scholar, 3Kliza K. Husnjak Resolving complexity networks.Front. Mol. Biosci. 2020; 7: 21Crossref (22) 4Callis J. machinery system.Arabidopsis Book. 2014; 12e0174Crossref Each different chains unique structure, thus providing opportunity single influence numerous pathways, other than degradation, DNA damage repair translation trafficking 5Dittmar G. 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Wilkinson K.D. roles ubiquitin-specific enzymes.Annu. 2009; 78: 363-397Crossref (967) adaptive nature signaling, frequently utilized function environmental changes stress (13Fang N.N. Zhu Rose A. Wu K.P. Mayor Deubiquitinase degradation misfolded cytosolic proteins upon heat-stress.Nat. Commun. 2016; 12907Crossref (34) 14Li Huang Xu Zhou L. Liang Gao C. Long CYLD negatively regulates high glucose NF-kappaB inflammatory mesangial cells.Biomed. Res. Int. 2017: 3982906Crossref (5) 15Cotto-Rios X.M. Békés Chapman Ueberheide B. T.T. Deubiquitinases target stress.Cell Rep. 2: 1475-1484Abstract Full Text PDF (115) 16Dai F. Lee Zhang Zhuang Yao Xi Xiao Z.D. You Li Su X. Gan BAP1 inhibits ER gene network modulates metabolic response.Proc. Natl. Acad. U. 114: 3192-3197Crossref (48) (Fig. 1), an E1 activating enzyme responsible ATP-dependent manner charging E2 conjugase (17Schulman B.A. Harper J.W. Ubiquitin-like activation enzymes: apex downstream signalling pathways.Nat. Cell Biol. 10: 319-331Crossref (514) then either transfers substrate E3 ligase transfer molecule (18Ye Building at work.Nat. 755-764Crossref (611) former case, brought into proximity associated A number exist (∼40 E2s over 600 E3s humans 12 ∼80 yeast), pairing determines ubiquitinated (19George A.J. Hoffiz Y.C. Charles Mabb A.M. comprehensive atlas mutations neurological disorders.Front. 2018; 9: 29Crossref (45) 20Stewart M.D. Ritterhoff Klevit R.E. Brzovic P.S. More just middle men.Cell 26: 423-440Crossref determining how assembled 21Metzger M.B. Pruneda J.N. Weissman RING-type ligases: Master manipulators ubiquitin-conjugating ubiquitination.Biochim. Biophys. Acta. 1843: 47-60Crossref (313) Protein commonly occurs via isopeptide between C-terminus lysine (22Rechsteiner Ubiquitin-mediated intracellular proteolysis.Annu. 1987; 3: 1-30Crossref Other forms nonlysine rare but exist, peptide bonds N-terminal methionine (M1), thioester residue, hydroxyester serine threonine residue (23McClellan Laugesen S.H. Ellgaard molecular non-lysine ubiquitination.Open 190147Crossref Furthermore, recently been shown be conjugated nonprotein surfaces such lipopolysaccharides (24Otten E.G. Werner E. Crespillo-Casado Boyle K.B. Dharamdasani V. Pathe Santhanam Randow Ubiquitylation lipopolysaccharide RNF213 bacterial infection.Nature. 2021; 594: 111-116Crossref (13) Once first substrate, second round conjugation linking two together (25Nonhoff Ralser Welzel Piccini I. Balzereit Yaspo M.L. Lehrach Krobitsch Ataxin-2 interacts DEAD/H-box RNA helicase DDX6 interferes P-bodies granules.Mol. Cell. 2007; 18: 1385-1396Crossref (230) linked polyubiquitin any seven residues (K6, K11, K27, K29, K33, K48, K63) well group M1 (26Akutsu Dikic Bremm glance.J. 129: 875-880Crossref (217) linkage sites provides archetype, while many can proteasome-dependent some extent, others serve array Proteomics data demonstrate types increase inhibition proteasome, K63-linked does not, suggesting it involved almost exclusively nonproteasomal (27Kim Bennett E.J. Huttlin E.L. Guo Possemato Sowa M.E. Rad R. Rush Comb Gygi S.P. Systematic quantitative assessment ubiquitin-modified proteome.Mol. 2011; 44: 325-340Abstract (1063) 28Xu P. Duong D.M. Seyfried N.T. Cheng Xie Robert Hochstrasser Finley Peng Quantitative proteomics reveals unconventional degradation.Cell. 137: 133-145Abstract (790) topologies may bound recognized distinct generate signals (29Husnjak Ubiquitin-binding proteins: Decoders ubiquitin-mediated functions.Annu. 291-322Crossref (459) Additionally, both homotypic chains, each same (e.g., K48-linked chains) heterotypic multiple (30Yau increasing code.Nat. 579-586Crossref produce branched themselves PTMs phosphorylation SUMOylation, further expanding possibilities 31Ohtake Tsuchiya emerging architecture.J. 161: 125-133PubMed While widely studied, significant advancement study responsive removal occurred. Humans encode ∼100 disassembling thereby signals, recycling (32Komander Clague Breaking Structure deubiquitinases.Nat. 550-563Crossref (1276) done cleaving monomers distal end entire breaking proximal (12Reyes-Turcu Similar conjugases, usually specific they bind (11Mevissen Since direct antagonists conjugation, results switch-like system levels therefore determined competing systems, expression, subcellular location, controlled interactions modifications (PTMs) 2) (33Sahtoe D.D. Sixma T.K. Layers regulation.Trends 40: 456-467Abstract (87) 34Zheng N. Shabek Structure, function, 129-157Crossref (415) E2s, E3s, respond cues induce prioritization generation (3Kliza stresses, regulation, those result active site large (35Lee J.G. Baek Soetandyo Reversible inactivation deubiquitinases vitro cells.Nat. 2013; 4: 1568Crossref (105) ability makes them interesting therapeutics. Indeed, dysregulation malfunction disorders, resulting aberrant within cell (36Kowalski J.R. Juo synaptic nervous diseases.Neural Plast. 2012: 892749Crossref (37) 37Fraile J.M. Quesada Rodriguez Freije Lopez-Otin cancer: New options.Oncogene. 31: 2373-2388Crossref (292) importance, small-molecule inhibitors selective being developed goal utilization treatments diseases (38Harrigan J.A. Jacq Martin N.M. Jackson Deubiquitylating drug discovery: Emerging opportunities.Nat. Drug Discov. 17: 57-78Crossref (241) Recent insights importance combined drugs potential, marked newly burgeoning field provided directions future studies come. As we learn about processes, gain emphasis signals. addition regulating generated essential maintain supply down synthesized fusion 1) (39Pickart C.M. I.A. carboxyl-terminal hydrolase amides.J. 1985; 260: 7903-7910Abstract 40Hanna Meides D.P. induces altered proteasome composition.Cell. 747-759Abstract (0) Constant maintenance free pool necessary homeostasis required, environment biomolecular incurred (41Park C.W. Ryu K.Y. dynamics homeostasis.BMB 47: 475-482Crossref (64) section highlight play cells. Table 1 summarizes class, family, all specifically discussed review.Table 1List mentioned classificationsDUB (∗known redox-sensitive)ClassFamilyKnown ub specificityKnown affectedA20∗Cysteine proteaseoutK63NF-κB (157Shembade Harhaj E.W. A20 deubiquitinase.Cell. Immunol. 123-130Crossref (123) Scholar)AMSHMetalloproteaseJAMM/MPN+K63Endocytosis/sorting (249Davies Paul L.N. Das Mechanism recruitment endosome-associated AMSH.Biochemistry. 52: 7818-7829Crossref (24) Scholar)AMSH-LPMetalloproteaseJAMM/MPN+K63Endocytosis/sorting Scholar)ATXN3Cysteine proteaseMJDK48, K63Protein (250Durcan T.M. Kontogiannea Thorarinsdottir Fallon Williams Djarmati Fantaneanu Paulson H.L. Fon E.A. Machado-Joseph disease-associated mutant ataxin-3 parkin stability.Hum. 20: 141-154Crossref 251Blount Tsou W.L. Ristic Burr A.A. Ouyang Galante Scaglione K.M. Todi S.V. 2 prevents interacting Rad23.Nat. 5: 4638Crossref (41) Scholar); ER-associated (252Zhong Pittman R.N. Ataxin-3 binds VCP/p97 retrotranslocation ERAD substrates.Hum. 2006; 15: 2409-2420Crossref (153) transcription (253Evert B.O. Araujo Vieira-Saecker de Vos R.A. Harendza Klockgether Wullner represses chromatin binding, interaction histone deacetylase 3, deacetylation.J. Neurosci. 11474-11486Crossref (121) cytoskeletal (254Rodrigues do Carmo Costa T.L. Ferreira Bajanca Logarinho Maciel Absence leads disorganization increased death.Biochim. 1803: 1154-1163Crossref (31) (255Pfeiffer Luijsterburg M.S. Acs Wiegant W.W. Helfricht Herzog L.K. Minoia Bottcher Salomons F.A. van Attikum Dantuma N.P. consolidates MDC1-dependent double-strand break counteracting SUMO-targeted RNF4.EMBO 36: 1066-1083Crossref (36) Scholar)ATXN3LCysteine (256Ge Chen Qin Z. Liu Tan Zou Ren like (ATXN3L), member Josephin enzymes, promotes breast cancer proliferation Kruppel-like factor 5 (KLF5).Oncotarget. 21369-21378Crossref Scholar)BAP1Cysteine proteaseUCHK48DNA repair/transcription (257Yu Pak Hammond-Martel Ghram Rodrigue Daou Barbour Corbeil Hebert Drobetsky Masson J.Y. Di Noia Affar El Tumor suppressor repair.Proc. 111: 285-290Crossref (210) 258Okino Machida Frankland-Searby Y.J. BRCA1-associated (BAP1) antagonizes FoxK2 genes.J. 290: 1580-1591Abstract Scholar)BRCC36MetalloproteaseJAMM/MPN+K63DNA repair/cell cycle (259Wang Hurov Hofmann Elledge S.J. NBA1, new player Brca1 complex, resistance checkpoint control.Genes Dev. 23: 729-739Crossref (134) 260Yan Wang Hong Yang Lin He Q. Zheng Tang Yin Shao complex BRISC proper mitotic spindle assembly mammalian cells.J. 210: 209-224Crossref (29) Scholar)Cezanne∗Cysteine proteaseoutK11, K63NF-κB (261Hu Brittain G.C. Chang J.H. Puebla-Osorio Jin Zal Fu Y.X. Sun S.C. OTUD7B controls non-canonical deubiquitination TRAF3.Nature. 494: 371-374Crossref (133) Scholar)CSN5MetalloproteaseJAMM/MPN+K63DNA (262Pan Claret F.X. Jab1/CSN5 response, repair, cancer.Cancer Ther. 256-262Crossref (263Shackleford T.J. JAB1/CSN5: control cancer.Cell Div. 26Crossref (103) sorting (264Liu Shah Xiang Deng Z.B. Edmonds Jambor Kappes J.C. H.G. COP9-associated CSN5 exosomal sorting.Am. Pathol. 174: 1415-1425Abstract Scholar)CYLDCysteine proteaseoutK63, M1Cell (265Wickstrom S.A. Masoumi K.C. Khochbin Fassler Massoumi cell-cycle progression inactivating HDAC6 acetylated tubulin.EMBO 29: 131-144Crossref (104) NF-κB/WNT (266Komander tidies up dishevelled signaling.Mol. 37: 589-590Abstract 267Sun CYLD: tumor biological processes.Cell Death Differ. 25-34Crossref (268) Scholar)JOSD1Cysteine K63Endocytosis; (268Seki Gong Sakai JosD1, membrane-targeted enzyme, activated dynamics, motility, endocytosis.J. 288: 17145-17155Abstract Scholar)JOSD2Cysteine K63Metabolism (269Krassikova Nagarajan Queiroz A.L. Kacal Samakidis Vakifahmetoglu-Norberg Norberg JOSD2 positive regulator metabolism.Cell 28: 1091-1109Crossref (1) Scholar)MINDY1Cysteine proteaseMINDYK48Self-renewal stem cells (270James Zhao T.Y. Rahim Saxena Muthalif N.A. Uemura Tsuneyoshi Ong Igarashi Lim C.Y. Dunn N.R. Vardy L.A. MINDY1 polyamines embryonic self-renewal.Stem Cells. 1170-1178Crossref (8) Scholar)MINDY2Cysteine proteaseMINDYNon-specificMINDY3Cysteine proteaseMINDYK48MINDY4Cysteine proteaseMINDYK48MINDY4BCysteine proteaseMINDYK48MYSM1MetalloproteaseJAMM/MPN+K63Transcription (271Zhu Puc Ohgi K.A. Erdjument-Bromage Tempst Glass C.K. Rosenfeld M.G. H2A coordinating acetylation H1 dissociation transcriptional regulation.Mol. 27: 609-621Abstract immune (272Jiang X.X. Chou Jones Sanchez X.F. S.Y. Epigenetic antibody responses MYSM1.Sci. 13755Crossref Scholar)OTUB1∗Cysteine proteaseoutK48DNA (273Wu Gu OTUB1 stabilizes mismatch MSH2 blocking ubiquitination.J. 296: 100466Abstract (274Zhou Yu Manyam Schluns Otub1 CD8(+) T NK IL-15-mediated priming.Nat. 879-889Crossref Scholar)OTUB2Cysteine K63DNA (275Kato Nakajima Ui Muto-Terao Ogiwara Nakada Fine-tuning damage-dependent OTUB2 supports choice.Mol. 53: 617-630Abstract (56) (276Li X.Y. Mao X.Q. Han Q.Q. Jiang L.X. Qiu Y.M. Dai Gli2 stability OTUB2.Biochem. 505: 113-118Crossref (3) (124Garshott Sundaramoorthy Leonard Distinct ribosomal ubiquitylation events hierarchically organized.Elife. 9e54023Crossref (16) Scholar)OTUD1∗Cysteine proteaseoutK63Translation (277Lu Song Qi McNutt M.A. Mutations OTUD1 autoimmune disorders.J. Autoimmun. 94: 156-165Crossref Scholar)OTUD2∗Cysteine sorting; unfolded (278Ernst Mueller Ploegh Schlieker otubain YOD1 associates p97 facilitate dislocation ER.Mol. 28-38Abstract Scholar)OTUD3∗Cysteine proteaseoutK6, K48Translation (279Zhang Fang Ling Chu Zang et al.Acetylation-dependent OTUD3 MAVS innate antiviral immunity.Mol. 79: 304-319.e307Abstract Scholar)OTUD5∗Cysteine proteaseoutK48, K63Cell (280Cho Kim Park Kwon M.H. S.B. B.C. S.G. OTUD5 mTORC1 mTORC2 pathways.Cell 900-914Crossref (2) 281Park Choi H.K. Kwak Yoon mediates sequential PDCD5 p53 genotoxic stress.Cancer Lett. 357: 419-427Crossref (282Guo Kong Cai Ma Yi al.OTUD5 antitumor immunity stab

Язык: Английский

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Ubiquitin—A structural perspective

Molecular Cell, Год журнала: 2025, Номер 85(2), С. 323 - 346

Опубликована: Янв. 1, 2025

Язык: Английский

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Post-Translational Modifications of G Protein–Coupled Receptors Control Cellular Signaling Dynamics in Space and Time

Pharmacological Reviews, Год журнала: 2020, Номер 73(1), С. 120 - 151

Опубликована: Дек. 2, 2020

G protein–coupled receptors (GPCRs) are a large family comprising >800 signaling that regulate numerous cellular and physiologic responses. GPCRs have been implicated in diseases represent the largest class of drug targets. Although advances GPCR structure pharmacology improved discovery, regulation function by diverse post-translational modifications (PTMs) has received minimal attention. Over 200 PTMs known to exist mammalian cells, yet only few reported for GPCRs. Early studies revealed phosphorylation as major regulator signaling, whereas later reports ubiquitination, glycosylation, palmitoylation biology. our knowledge is extensive, modifying enzymes, regulation, other limited. In this review we provide comprehensive overview with greater focus on new discoveries. We discuss subcellular location regulatory mechanisms control The functional implications newly discovered receptor folding, biosynthesis, endocytic trafficking, dimerization, compartmentalized biased also provided. Methods detect study well PTM crosstalk further highlighted. Finally, conclude discussion human disease their importance discovery.

Significance Statement

Post-translational modification controls all aspects function; however, detection types A thorough understanding role which trafficking essential dysregulated improving refining development

Язык: Английский

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Ubiquitomics: An Overview and Future

Biomolecules, Год журнала: 2020, Номер 10(10), С. 1453 - 1453

Опубликована: Окт. 17, 2020

Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is key post-translational modification that determines the fate, function, and turnover most cellular proteins. Ubiquitin exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected lysine, perhaps other amino acid side chains, N-termini proteins, often including branching chains. Understanding this enormous complexity in ubiquitination, so-called ‘ubiquitin code’, combination with ∼1000 enzymes involved controlling recognition, conjugation, deconjugation, calls for novel developments analytical techniques. Here, we review different headways field mainly driven by mass spectrometry chemical biology, referred “ubiquitomics”, aiming understand system’s biological diversity.

Язык: Английский

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Squalene monooxygenase: a journey to the heart of cholesterol synthesis

Progress in Lipid Research, Год журнала: 2020, Номер 79, С. 101033 - 101033

Опубликована: Апрель 28, 2020

Язык: Английский

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Alternative systems for misfolded protein clearance: life beyond the proteasome

FEBS Journal, Год журнала: 2020, Номер 288(15), С. 4464 - 4487

Опубликована: Ноя. 2, 2020

Protein misfolding is a major driver of ageing‐associated frailty and disease pathology. Although all cells possess multiple, well‐characterised protein quality control systems to mitigate the toxicity misfolded proteins, how they are integrated maintain homeostasis (‘proteostasis’) in health—and their disintegration contributes disease—is still an exciting fast‐paced area research. Under physiological conditions, predominant route for clearance involves ubiquitylation proteasome‐mediated degradation. When capacity this overwhelmed—as happens during conditions acute environmental stress, or chronic ageing‐related decline—alternative routes activated. In review, we summarise our current understanding proteasome‐targeted proteins retrafficked alternative such as juxta‐nuclear sequestration selective autophagy when ubiquitin–proteasome system compromised. We also discuss molecular determinants these systems, attempt clarify distinctions between various cytoplasmic spatial inclusion bodies (e.g., Q‐bodies, p62 bodies, JUNQ, aggresomes, aggresome‐like induced structures ‘ALIS’), speculate on emerging concepts field that hope will spur future research—with potential benefit rational development healthy ageing strategies.

Язык: Английский

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A new dawn beyond lysine ubiquitination

Nature Chemical Biology, Год журнала: 2022, Номер 18(8), С. 802 - 811

Опубликована: Июль 27, 2022

Язык: Английский

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