Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation

Deol, Kirandeep K.; Crowe, Sean O.; Du, Jiale; Bisbee, Heather A.; Guenette, Robert G.; Strieter, Eric R.

doi:10.1016/j.molcel.2020.10.017

Cited by 54 publications

(76 citation statements)

References 93 publications

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“…Together, our data identify TRABID-HECTD1 as the first DUB-E3 pair regulating K29-linked polyubiquitin chains. Interestingly, a recent study has shown that the proteasomal subunit RPN13 acts as an accessory protein to enhance the activity of the DUB UCH37 toward K48-containing, branched triubiquitin, and this could provide new ways to further explore the assembly/disassembly of these more complex ubiquitin chain types ( 85 ). The ability of some E3s to form branched ubiquitin chains, combined with this recent report of a debranching DUB activity, further exemplifies the versatility of protein ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

Harris

Pen

Scholz

et al. 2021

Journal of Biological Chemistry

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Ubiquitin is a versatile posttranslational modification, which is covalently attached to protein targets either as a single moiety or as a ubiquitin chain. In contrast to K48 and K63-linked chains, which have been extensively studied, the regulation and function of most atypical ubiquitin chains are only starting to emerge. The deubiquitinase TRABID/ZRANB1 is tuned for the recognition and cleavage of K29 and K33-linked chains. Yet, substrates of TRABID and the cellular functions of these atypical ubiquitin signals remain unclear. We determined the interactome of two TRABID constructs rendered catalytic dead either through a point mutation in the catalytic cysteine residue or through removal of the OTU catalytic domain. We identified 50 proteins trapped by both constructs and which therefore represent candidate substrates of TRABID. The E3 ubiquitin ligase HECTD1 was then validated as a substrate of TRABID and used UbiCREST and Ub-AQUA proteomics to show that HECTD1 preferentially assembles K29- and K48-linked ubiquitin chains. Further in vitro autoubiquitination assays using ubiquitin mutants established that while HECTD1 can assemble short homotypic K29 and K48-linked chains, it requires branching at K29/K48 in order to achieve its full ubiquitin ligase activity. We next used transient knockdown and genetic knockout of TRABID in mammalian cells in order to determine the functional relationship between TRABID and HECTD1. This revealed that upon TRABID depletion, HECTD1 is readily degraded. Thus, this study identifies HECTD1 as a mammalian E3 ligase that assembles branched K29/K48 chains and also establishes TRABID-HECTD1 as a DUB/E3 pair regulating K29 linkages.

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Section: Discussionmentioning

confidence: 99%

The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

Harris

Pen

Scholz

et al. 2021

Journal of Biological Chemistry

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“…Conversely, Ataxin-3 has been shown to tune CHIP activity via its DUB activity [ 100 ]. At the proteasome, the DUB Ubiquitin C-terminal Hydrolase 37 (UCH37) has also been shown to have a key role in disassembling complex heterotypic chains to allow for efficient protein degradation [ 101 ]. Given the emerging role for heterotypic chains in cytosolic protein QC, the activity of UCH37 may also have an important role in effective clearance of misfolded cytosolic proteins.…”

Section: Deubiquitinasesmentioning

confidence: 99%

It's not just a phase; ubiquitination in cytosolic protein quality control

Baker

Bernardini

2021

Biochemical Society Transactions

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The accumulation of misfolded proteins is associated with numerous degenerative conditions, cancers and genetic diseases. These pathological imbalances in protein homeostasis (termed proteostasis), result from the improper triage and disposal of damaged and defective proteins from the cell. The ubiquitin-proteasome system is a key pathway for the molecular control of misfolded cytosolic proteins, co-opting a cascade of ubiquitin ligases to direct terminally damaged proteins to the proteasome via modification with chains of the small protein, ubiquitin. Despite the evidence for ubiquitination in this critical pathway, the precise complement of ubiquitin ligases and deubiquitinases that modulate this process remains under investigation. Whilst chaperones act as the first line of defence against protein misfolding, the ubiquitination machinery has a pivotal role in targeting terminally defunct cytosolic proteins for destruction. Recent work points to a complex assemblage of chaperones, ubiquitination machinery and subcellular quarantine as components of the cellular arsenal against proteinopathies. In this review, we examine the contribution of these pathways and cellular compartments to the maintenance of the cytosolic proteome. Here we will particularly focus on the ubiquitin code and the critical enzymes which regulate misfolded proteins in the cytosol, the molecular point of origin for many neurodegenerative and genetic diseases.

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“…In eukaryotes, K29/K48 branched chains have so far been demonstrated to play a role in targeting substrates to the UPS and ERAD (160,161). Interestingly, the UPS appears wellequipped for processing these more complex chains, with a recent study showing that the proteasome-associated DUB UCH37 is a debranching DUB with important roles during proteasomal degradation (162). Through continued advancements in mass spectrometry-based techniques including the quantification of polyubiquitin linkage composition (e.g.…”

Section: The Ubiquitin Codementioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

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Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation

Cited by 54 publications

References 93 publications

The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

It's not just a phase; ubiquitination in cytosolic protein quality control

Targeting the Ubiquitin System in Glioblastoma

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