Specificity and disease in the ubiquitin system

Chaugule, Viduth K.; Walden, Helen

doi:10.1042/bst20150209

Cited by 50 publications

(41 citation statements)

References 232 publications

(243 reference statements)

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“…As a result, targeting these enzymes may offer opportunities for fine-tuning inflammatory signaling processes for therapeutic benefits in infectious diseases and metabolic, autoimmune and autoinflammatory disorders. 52, 53 …”

Section: Introductionmentioning

confidence: 99%

Post-translational regulation of inflammasomes

2016

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Inflammasomes play essential roles in immune protection against microbial infections. However, excessive inflammation is implicated in various human diseases, including autoinflammatory syndromes, diabetes, multiple sclerosis, cardiovascular disorders and neurodegenerative diseases. Therefore, precise regulation of inflammasome activities is critical for adequate immune protection while limiting collateral tissue damage. In this review, we focus on the emerging roles of post-translational modifications (PTMs) that regulate activation of the NLRP3, NLRP1, NLRC4, AIM2 and IFI16 inflammasomes. We anticipate that these types of PTMs will be identified in other types of and less well-characterized inflammasomes. Because these highly diverse and versatile PTMs shape distinct inflammatory responses in response to infections and tissue damage, targeting the enzymes involved in these PTMs will undoubtedly offer opportunities for precise modulation of inflammasome activities under various pathophysiological conditions.

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Section: Introductionmentioning

confidence: 99%

Post-translational regulation of inflammasomes

2016

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“…Using ATP to fuel the process, E1 adenylates ubiquitin to create a high energy E1-ubiquitin thionene [16]. There are only two types of E1 enzymes, but each type can interact with one of the approximately three dozen E2 enzymes to continue the cascade [17]. This is important to help maintain the precise regulation necessary for the UPS to function.…”

Section: Introductionmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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“…The Caenorhabditis elegans homolog, UBC-18, is implicated in developmental processes through its cooperation with the RBR E3 ARI-1 (3). UBCH7 has been shown to regulate S-phase transition of the cell cycle in human cell culture (4); however, to date, it is mainly the multisubunit RING-type E3s known as Cullin-RING ligases (CRLs) associated with substrate ubiquitination that control cell cycle progression (5)(6)(7). Because UBCH7 is unable to work directly with RING E3s, including the CRLs, how it performs its role during regulation of the cell cycle is unclear.…”

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confidence: 99%

Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development

Dove

Kemp

Bona

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Ubiquitination, the crucial posttranslational modification that regulates the eukaryotic proteome, is carried out by a trio of enzymes, known as E1 [ubiquitin (Ub)-activating enzyme], E2 (Ub-conjugating enzyme), and E3 (Ub ligase). Although most E2s can work with any of the three mechanistically distinct classes of E3s, the E2 UBCH7 is unable to function with really interesting new gene (RING)-type E3s, thereby restricting it to homologous to E6AP C-terminus (HECT) and RING-in-between-RING (RBR) E3s. The Caenorhabditis elegans UBCH7 homolog, UBC-18, plays a critical role in developmental processes through its cooperation with the RBR E3 ARI-1 (HHARI in humans). We discovered that another E2, ubc-3, interacts genetically with ubc-18 in an unbiased genome-wide RNAi screen in C. elegans. These two E2s have nonoverlapping biochemical activities, and each is dedicated to distinct classes of E3s. UBC-3 is the ortholog of CDC34 that functions specifically with Cullin-RING E3 ligases, such as SCF (Skp1-Cullin-F-box). Our genetic and biochemical studies show that UBCH7 (UBC-18) and the RBR E3 HHARI (ARI-1) coordinate with CDC34 (UBC-3) and an SCF E3 complex to ubiquitinate a common substrate, a SKP1-related protein. We show that UBCH7/HHARI primes the substrate with a single Ub in the presence of CUL-1, and that CDC34 is required to build chains onto the Ub-primed substrate. Our study reveals that the association and coordination of two distinct E2/E3 pairs play essential roles in a developmental pathway and suggests that cooperative action among E3s is a conserved feature from worms to humans.

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Specificity and disease in the ubiquitin system

Cited by 50 publications

References 232 publications

Post-translational regulation of inflammasomes

Post-translational regulation of inflammasomes

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development

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