Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling

Han, Wonhee; Lee, Hye-Yoon; Han, Jin‐Kwan

doi:10.1038/srep42590

Cited by 20 publications

(20 citation statements)

References 61 publications

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“…Uch37 has been implicated in DNA replication and cell cycle [141], TGF-β signaling [142–145], WNT signaling via Tcf7 [146], longevity [147], cell migration and invasion [148], and the reversal of ubiquitination of proteasome subunits [138]. It is difficult to resolve common themes from the physiological studies reported to date.…”

Section: Physiological Functionmentioning

confidence: 99%

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Poot

Tian

Finley

2017

Journal of Molecular Biology

107

115

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Three deubiquitinating enzymes–Rpn11, Usp14, and Uch37–are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel’s entry port, where they can impede further translocation. Rpn11, situated over the port, can remove these chains without compromising degradation because substrates must be irreversibly committed to degradation before Rpn11 acts. This coupling between deubiquitination and substrate degradation is ensured by the Ins-1 loop of Rpn11, which controls ubiquitin access to its catalytic site. In contrast to Rpn11, Usp14 and Uch37 can rescue substrates from degradation by promoting substrate dissociation from the proteasome prior to the commitment step. Uch37 is unique in being a component of both the proteasome and a second multisubunit assembly, the INO80 complex. However, only recruitment into the proteasome activates Uch37. Recruitment to the proteasome likewise activates Usp14. However, the influence of Usp14 on the proteasome depends on the substrate, due to its marked preference for proteins that carry multiple ubiquitin chains. Usp14 exerts complex control over the proteasome, suppressing proteasome activity even when inactive in deubiquitination. A major challenge for the field will be to elucidate the specificities of Rpn11, Usp14, and Uch37 in greater depth, employing not only model in vitro substrates, but their endogenous targets.

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Section: Physiological Functionmentioning

confidence: 99%

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Poot

Tian

Finley

2017

Journal of Molecular Biology

107

115

View full text Add to dashboard Cite

show abstract

“…On the other hand, positive UCH37 expression was also reported as a prognostic marker for increased patient survival in colorectal cancer, pancreatic ductal adenocarcinoma, and gastric cancer [ 89 , 90 , 91 ]. At the molecular and cellular level, UCH37 is involved in a number of crucial signaling pathways for the regulation of cellular growth and fate, including TGF-β signaling, Wnt signaling, Hedgehog signaling, apoptosis, DNA replication/cell cycle and cell migration/invasion [ 92 , 93 , 94 , 95 , 96 ]. For example, UCH37’s binding to Smoothened (Smo) counteracts Smo ubiquitination and leads to the stabilization of the Smo protein and the activation of the Hedgehog signaling pathway [ 95 ].…”

Section: Uch37: a Cryptic And Editing Deubiquitinasementioning

confidence: 99%

Deubiquitination Reactions on the Proteasome for Proteasome Versatility

Shin

Muniyappan

Tran

et al. 2020

IJMS

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The 26S proteasome, a master player in proteolysis, is the most complex and meticulously contextured protease in eukaryotic cells. While capable of hosting thousands of discrete substrates due to the selective recognition of ubiquitin tags, this protease complex is also dynamically checked through diverse regulatory mechanisms. The proteasome’s versatility ensures precise control over active proteolysis, yet prevents runaway or futile degradation of many essential cellular proteins. Among the multi-layered processes regulating the proteasome’s proteolysis, deubiquitination reactions are prominent because they not only recycle ubiquitins, but also impose a critical checkpoint for substrate degradation on the proteasome. Of note, three distinct classes of deubiquitinating enzymes—USP14, RPN11, and UCH37—are associated with the 19S subunits of the human proteasome. Recent biochemical and structural studies suggest that these enzymes exert dynamic influence over proteasome output with limited redundancy, and at times act in opposition. Such distinct activities occur spatially on the proteasome, temporally through substrate processing, and differentially for ubiquitin topology. Therefore, deubiquitinating enzymes on the proteasome may fine-tune the degradation depending on various cellular contexts and for dynamic proteolysis outcomes. Given that the proteasome is among the most important drug targets, the biology of proteasome-associated deubiquitination should be further elucidated for its potential targeting in human diseases.

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“…In vitro analysis revealed that UCHL5 can inhibit migration and invasion of glioma cells mediated via a downregulation of SNRPF [142]. It was reported that UCHL5 deubiquitinates Tcf3, which helps it to fully activate the Wnt/β-catenin pathway [143]. Furthermore, the region of UCHL5 amino acid residues from 313-329 interacts with proteasomal receptor ADRM1 [144], and, according to our analysis, this ADRM1 binding region of UCHL5 is the part of disorder-based protein binding region (see Table 3).…”

Section: Intrinsic Disorder In Ubiquitin C-terminal Hydrolase Isozymementioning

confidence: 99%

Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

et al. 2020

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The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

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Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling

Cited by 20 publications

References 61 publications

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Deubiquitination Reactions on the Proteasome for Proteasome Versatility

Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

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