Overexpression of USP14 Protease Reduces I-κB Protein Levels and Increases Cytokine Release in Lung Epithelial Cells

Mialki, Rachel K.; Zhao, Jing; Wei, Jianxin; Mallampalli, Daniel F; Zhao, Yutong

doi:10.1074/jbc.c112.446682

Cited by 65 publications

(54 citation statements)

References 25 publications

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“…Usp14 activity is elevated in LPS-treated-cells, in parallel with its phosphorylation, possibly by AKT [74,75]. These and other observations suggest an anti-inflammatory effect of Usp14 inhibition [74–78]. …”

Section: Enzymatic Activity and Its Regulationmentioning

confidence: 90%

“…Indeed, phosphorylation of Usp14 (or the use of a Usp14 phosphomimetic) results in increased activity in assays with the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC), for both Usp14 in isolation and Usp14 in the proteasome, suggesting that phosphorylation and proteasome binding activate Usp14 via unrelated mechanisms [73]. Usp14 activity is elevated in LPS-treated-cells, in parallel with its phosphorylation, possibly by AKT [74,75]. These and other observations suggest an anti-inflammatory effect of Usp14 inhibition [74–78].…”

Section: Enzymatic Activity and Its Regulationmentioning

confidence: 99%

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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.

show abstract

Section: Enzymatic Activity and Its Regulationmentioning

confidence: 90%

Section: Enzymatic Activity and Its Regulationmentioning

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

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“…We have shown that ubiquitin-specific protease (USP) 14 modulates I-κB levels (Mialki et al, 2013). Little is known about the role of USPs in the regulation of GPCR stability.…”

Section: Introductionmentioning

confidence: 99%

Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury

et al. 2016

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Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.

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“…Up-expression of miR-4782-3p is related with favorable prognosis in NSCLC cells through decreasing the USP14 expression [73]. Although USP14 usually plays an inhibitory role in protein degradation, overexpression of USP14 induced I-κB degradation by linking RelA, the binding partner of I-κB, leading to increased cytokine release in lung epithelial cells [74]. …”

Section: Introductionmentioning

confidence: 99%

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

et al. 2015

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Copper and gold complexes have clinical activity in several diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is associated with targeting the 19S proteasome-associated deubiquitinases (DUBs), UCHL5 and USP14. Here we discuss metal DUB inhibitors in treating cancer and other diseases. (from Editor). Several copper and gold complexes have clinical activity in treating some human diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is tightly associated with their ability to target and inhibit the 19S proteasome-associated deubiquitinases (DUBs), UCHL5 and USP14. In this article we review small molecule inhibitors of DUBs and 19S proteasome-associated DUBs. We then describe and discuss the ubique nature of CuPT and auranofin, which is inhibition of 19S proteasome-associated UCHL5 and USP14. We finally suggest the potential to develop novel, specific metal-based DUB inhibitors for treating cancer and other diseases

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Overexpression of USP14 Protease Reduces I-κB Protein Levels and Increases Cytokine Release in Lung Epithelial Cells

Cited by 65 publications

References 25 publications

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

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