Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Tanno, Hidetaka; Shigematsu, Takeshi; Nishikawa, Shuhei; Hayakawa, Akira; Denda, Kimitoshi; Tanaka, Toshiaki; Komada, Masayuki

doi:10.1074/jbc.m113.528372

Cited by 22 publications

(40 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified USP37 as a novel interactor of HBx. Interestingly, in contrast to the earlier reports on nuclear distribution of USP37 [32] , we found that USP37 co-localized with HBx in the cytoplasm through a chaperoning mechanism. Many recent studies have highlighted the significant role of E3 ubiquitin ligases, deubiquitinases or substrate translocation between cell compartments, leading to substrate stability motivated us to explore the effect of HBx-driven exodus of USP37 from the nucleus vis-à-vis its intracellular stability.…”

Section: Discussioncontrasting

confidence: 99%

See 1 more Smart Citation

The HBx Oncoprotein of Hepatitis B Virus Deregulates the Cell Cycle by Promoting the Intracellular Accumulation and Re-Compartmentalization of the Cellular Deubiquitinase USP37

Saxena

Kumar

2014

PLoS ONE

View full text Add to dashboard Cite

The HBx oncoprotein of hepatitis B Virus has been accredited as one of the protagonists in driving hepatocarcinogenesis. HBx exerts its influence over the cell cycle progression by potentiating the activity of cyclin A/E-CDK2 complex, the Cyclin A partner of which is a well-known target of cellular deubiquitinase USP37. In the present study, we observed the intracellular accumulation of cyclin A and USP37 proteins under the HBx microenvironment. Flow cytometry analysis of the HBx-expressing cells showed deregulation of cell cycle apparently due to the enhanced gene expression and stabilization of USP37 protein and deubiquitination of Cyclin A by USP37. Our co-immunoprecipitation and confocal microscopic studies suggested a direct interaction between USP37 and HBx. This interaction promoted the translocation of USP37 outside the nucleus and prevented its association and ubiquitination by E3 ubiquitin ligases - APC/CDH1 and SCF/β-TrCP. Thus, HBx seems to control the cell cycle progression via the cyclin A-CDK2 complex by regulating the intracellular distribution and stability of deubiquitinase USP37.

show abstract

Section: Discussioncontrasting

confidence: 99%

“…USP37 has been reported previously to majorly localize in the nucleoplasm [32] . However, we observed that under HBx environment, USP37 translocated in the peri-nuclear-cytoplasmic region and co-localized with HBx (Pearson’s co-efficient of correlation = 0.994292; Mander’s co-efficient of correlation = 0.658119; n = 25).…”

Section: Resultsmentioning

confidence: 92%

The HBx Oncoprotein of Hepatitis B Virus Deregulates the Cell Cycle by Promoting the Intracellular Accumulation and Re-Compartmentalization of the Cellular Deubiquitinase USP37

Saxena

Kumar

2014

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…S1E). As a control, the UIM region of USP37 equally pulled down Lys48- and Lys63-linked ubiquitin chains as reported22. Introduction of mutations into either UIM1 or UIM2 led to almost complete loss of binding to Lys48 ubiquitin chains, indicating that the tandem UIMs play a cooperative role in ubiquitin binding.…”

Section: Resultssupporting

confidence: 70%

“…Co-immunoprecipitation experiments in cells expressing the K48R or K63R mutant of ubiquitin demonstrated that USP25 binds more effectively to Lys48-, than to Lys63-, polyubiquitinated proteins also in the cell. Previous studies have shown that several UIMs, such as those in Hrs28, Rap802024, and Ankrd1321, bind to Lys63-linked ubiquitin chains specifically, while others, such as those in ataxin-3 7 and USP3722, bind to Lys48- and Lys63-linked chains with similar affinity. In contrast, reports of UIMs with binding specificity/preference to Lys48 ubiquitin chains have been limited.…”

Section: Discussionmentioning

confidence: 99%

Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP25

Kawaguchi

Tanaka

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Ubiquitin-specific protease (USP) 25, belonging to the USP family of deubiquitinases, harbors two tandem ubiquitin-interacting motifs (UIMs), a ~20-amino-acid α-helical stretch that binds to ubiquitin. However, the role of the UIMs in USP25 remains unclear. Here we show that the tandem UIM region binds to Lys48-, but not Lys63-, linked ubiquitin chains, where the two UIMs played a critical and cooperative role. Purified USP25 exhibited higher ubiquitin isopeptidase activity to Lys48-, than to Lys63-, linked ubiquitin chains. Mutations that disrupted the ubiquitin-binding ability of the tandem UIMs resulted in a reduced ubiquitin isopeptidase activity of USP25, suggesting a role for the UIMs in exerting the full catalytic activity of USP25. Moreover, when mutations that convert the binding preference from Lys48- to Lys63-linked ubiquitin chains were introduced into the tandem UIM region, the USP25 mutants acquired elevated and reduced isopeptidase activity toward Lys63- and Lys48-linked ubiquitin chains, respectively. These results suggested that the binding preference of the tandem UIMs toward Lys48-linked ubiquitin chains contributes not only to the full catalytic activity but also to the ubiquitin chain substrate preference of USP25, possibly by selectively holding the Lys48-linked ubiquitin chain substrates in the proximity of the catalytic core.

show abstract

“…As shown in the left panel of Figure 3G , endogenous 14-3-3γ was localized in both the cytoplasm and the nucleoplasm. However, the localization of 14-3-3γ was altered in the nucleus when USP37 was overexpressed, showing co-localization (Figure 3G , right panel) [ 24 , 25 ]. As the sequences of 14-3-3 isoforms are similar, we investigated whether the other six known isoforms of 14-3-3 interacted with USP37.…”

Section: Resultsmentioning

confidence: 99%

Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3γ

et al. 2015

View full text Add to dashboard Cite

14-3-3 is a family of highly conserved protein that is involved in a number of cellular processes. In this study, we identified that the high expression of 14-3-3γ in various cancer cell lines correlates with the invasiveness of the cancer cells. Overexpression of 14-3-3γ causes changes to the morphologic characteristics of cell transformation, and promotes cell migration and invasion. The cells overexpressed with 14-3-3γ have been shown to stimulate foci and tumor formation in SCID-NOD mice in concert with signaling components as reported with the 14-3-3β. In our previous study, we demonstrated that 14-3-3γ inhibits apoptotic cell death and mediates the promotion of cell proliferation in immune cell lines. Earlier, binding partners for 14-3-3γ were defined by screening. We found that USP37, one of deubiquitinating enzymes (DUBs), belongs to this binding partner group. Therefore, we investigated whether 14-3-3γ mediates proliferation in cancer cells, and 14-3-3γ by USP37 is responsible for promoting cell proliferation. Importantly, we found that USP37 regulates the stability of ubiquitin-conjugated 14-3-3γ through its catalytic activity. This result implies that the interactive behavior between USP37 and 14-3-3γ could be involved in the regulation of 14-3-3γ degradation. When all these findings are considered together, USP37 is shown to be a specific DUB that prevents 14-3-3γ degradation, which may contribute to malignant transformation via MAPK signaling pathway, possibly providing a new target for therapeutic objectives of cancer.

show abstract

Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Cited by 22 publications

References 28 publications

The HBx Oncoprotein of Hepatitis B Virus Deregulates the Cell Cycle by Promoting the Intracellular Accumulation and Re-Compartmentalization of the Cellular Deubiquitinase USP37

The HBx Oncoprotein of Hepatitis B Virus Deregulates the Cell Cycle by Promoting the Intracellular Accumulation and Re-Compartmentalization of the Cellular Deubiquitinase USP37

Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP25

Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3γ

Contact Info

Product

Resources

About