Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets

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Key Points

Ubiquitin is a highly conserved 76 amino-acid protein that covalently attaches to protein substrates targeted for degradation by the 26S proteasome. The coordinated effort of a series of enzymes, including an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), uses ATP to ultimately form an isopeptide bond between ubiquitin and a substrate.
Another class of enzymes called deubiquitylating enzymes (DUBs) deconstruct these linkages and also have an essential role in ubiquitin function. In addition, ubiquitin-like proteins (UBLs), including NEDD8, SUMO and ISG15, share a characteristic three-dimensional fold with ubiquitin but have their own dedicated enzyme cascades and distinct (although sometimes overlapping) biological functions.
The ubiquitin–proteasome system (UPS) and UBL conjugation pathways have important roles in various human diseases, including numerous types of cancer, cardiovascular disease, viral diseases and neurodegenerative disorders. The proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals) is the first clinically validated drug to target the UPS and is approved for the treatment of multiple myeloma. This suggests that other diseases may conceivably be targeted by modulating components of the UPS and UBL conjugation pathways using small-molecule inhibitors.
A significant hurdle to identifying drug-like inhibitors of enzyme targets within the UPS and UBL conjugation pathways is the limited understanding of the molecular mechanisms and biological consequences of UBL conjugation.
Here, we provide an overview of the enzyme classes in the UPS and UBL pathways that are potential therapeutic targets, and highlight considerations that are important for drug discovery. We also discuss the progress in the development of small-molecule inhibitors, and review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention.

Abstract

The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis, and their functional importance in various diseases, including cancer, cardiovascular disease and neurodegenerative disorders, is now beginning to emerge. Brownell and colleagues review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention.

Abstract

The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.

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Most cited references 124

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Defining the human deubiquitinating enzyme interaction landscape.

Mathew Sowa, Eric J Bennett, Steven Gygi … (2009)

Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.

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The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins.

Camilla Raiborg, Harald Stenmark (2009)

Selective trafficking of membrane proteins to lysosomes for destruction is required for proper cell signalling and metabolism. Ubiquitylation aids this process by specifying which proteins should be transported to the lysosome lumen by the multivesicular endosome pathway. The endosomal sorting complex required for transport (ESCRT) machinery sorts cargo labelled with ubiquitin into invaginations of endosome membranes. Then, through a highly conserved mechanism also used in cytokinesis and viral budding, it mediates the breaking off of the cargo-containing intraluminal vesicles from the perimeter membrane. The involvement of the ESCRT machinery in suppressing diseases such as cancer, neurodegeneration and infections underscores its importance to the cell.

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Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.

Francisca E. Reyes-Turcu, Karen Ventii, Keith Wilkinson (2009)

Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin(-like) protein, and remodel polyubiquitin(-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Most DUB activity is cryptic, and conformational rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multiprotein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have led to new insights into the function of yeast and human DUBs. This review discusses ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes.

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Author and article information

Contributors

Lynn Bedford:

Bio :

Lynn Bedford is a senior research fellow of Parkinson's UK and was previously a junior research fellow of the UK Alzheimer's Research Trust. She was awarded these fellowships for her contribution to the understanding of the role of the ubiquitin–proteasome system in chronic neurodegenerative disease. She used gene targeting to show that neuropathological and behavioural features of dementia with Lewy bodies and Parkinson's disease could be recapitulated by the conditional ablation of a 26S proteasomal gene in the mouse brain that depletes neuronal content of 26S proteasomes.

James Lowe:

Bio :

James Lowe is Professor of Neuropathology an the University of Nottingham Medical School, UK, and Director of Medical Education. He has studied the role of the ubiquitin–proteasome system in chronic neurodegenerative diseases for 22 years. Using ubiquitin immunocytochemistry, he discovered (together with R.J.M.) that neuronal inclusions in neurodegenerative diseases contain ubiquitylated proteins. This discovery included cortical Lewy bodies, which contributed to the classification of dementia with Lewy bodies as a new neurodegenerative disease that is the second most common form of cognitive decline in the elderly after Alzheimer's disease.

Lawrence R. Dick:

Bio :

Lawrence R. Dick is Director of Biochemistry at Millennium Pharmaceuticals. He has studied the ubiquitin–proteasome system for over 22 years and worked as part of the teams that brought the proteasome inhibitor drug Velcade ^® (bortezomib) from an initial concept through to clinical application. The group he leads does research to enable the initiation of new drug discovery projects by designing assays to query targets, identify drug leads and understand the molecular mechanisms. The current focus of the group is on ubiquitin and ubiquitin-like protein conjugation pathways.

R. John Mayer:

Bio :

R. John Mayer is Emeritus Professor of Molecular Cell Biology at the University of Nottingham Medical School. He has studied intracellular proteolysis for 40 years. His introduction to this burgeoning field came by cellular protein microinjection studies that demonstrated that some injected proteins accumulated around the microtubule organizing centre in a protein sequestration site associated with intermediate filaments for protein degradation by autophagy. The detection of ubiquitylated proteins in all inclusions in chronic neurodegenerative diseases led to the hypothesis that neuronal 26S proteasomal malfunction would lead to neurodegeneration, which was proven by proteasomal gene targeting.

James E. Brownell: james.brownell@mpi.com

Bio :

James E. Brownell is a scientific fellow in the Discovery Oncology Department at Millennium Pharmaceuticals. He has conducted research on protein homeostasis for over 13 years and is presently working to identify inhibitors of ubiquitin-like protein conjugation pathways. He was part of the team that identified NEDD8 as a factor required for the ubiquitylation and degradation of the cullin-RING ligase substrates phospho-IκB and p27 ^Kip1 and that brought the NEDD8-activating enzyme (NAE) inhibitor MLN4924 from initial concept to its current stage as an experimental drug.

Journal

Journal ID (nlm-ta): Nat Rev Drug Discov

Journal ID (iso-abbrev): Nat Rev Drug Discov

Title: Nature Reviews. Drug Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1776

ISSN (Electronic): 1474-1784

Publication date (Electronic): 10 December 2010

Publication date (Print): 2011

Volume: 10

Issue: 1

Pages: 29-46

Affiliations

[1 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, School of Biomedical Sciences, University of Nottingham, ; NG7 2UH Nottingham UK

[2 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, School of Molecular Medical Sciences, University of Nottingham, ; NG7 2UH Nottingham UK

[3 ]GRID grid.419849.9, ISNI 0000 0004 0447 7762, Millennium Pharmaceuticals, ; 40 Landsdowne Street, Cambridge, 02139 Massachusetts USA

Article

Publisher ID: BFnrd3321

DOI: 10.1038/nrd3321

PMC ID: 7097807

PubMed ID: 21151032

SO-VID: d1ccdd71-8c60-4e61-b421-10521ae31b93

License:

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