Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation

Wei, Jianxin; Dong, Shuying; Bowser, Rachel K.; Khoo, Andrew; Zhang, Lina; Jacko, Anastasia M.; Zhao, Yutong; Zhao, Jing

doi:10.1126/scisignal.aak9660

Cited by 34 publications

(36 citation statements)

References 41 publications

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“…F-box protein, a component of SCF E3 ligase complex, can specifically recognize substrates (5,7,9). We have demonstrated that FBXL19 played an antiinflammatory role by targeting IL-33 receptor (ST2L) (13) and a histone acetyltransferase (CBP) (14). Further, a role of FBXL19 in the regulation of ubiquitination of Rho GTPases, such as RhoA (16), Rac1 (17), and Rac3 (15), has been revealed.…”

Section: Cbp Regulates Fbxl19 Acetylation and Stabilitymentioning

confidence: 99%

“…We have shown that CBP is a substrate of SCF FBXL19 E3 ligase (14). Overexpression of FBXL19 reduces CBP stability and mitigates CBP-mediated histone acetylation (14).…”

mentioning

confidence: 91%

“…Chen et al (11) and Liu et al (12) showed that SCF FBXO3 E3 ligase catalyzed FBXL2 ubiquitination. Recently, we demonstrated that a relatively new F-box protein, FBXL19, targets IL-33 receptor ST2L (13), an acetyltransferase CREB binding protein (CBP) (14), and small GTPases (15)(16)(17) for their ubiquitination and turnover within the proteasome system. However, the molecular regulation of FBXL19 stability has not been studied.…”

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confidence: 99%

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Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

et al. 2018

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Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation. FBXL19 is an unstable protein with a half-life of ∼3 h. FBXL19 can be polyubiquitinated, and the proteasome inhibitor MG-132 prolongs FBXL19 half-life, suggesting that FBXL19 degradation is mediated in the ubiquitin-proteasome system. FBXL19 can also be acetylated, and enhancing acetylation of FBXL19 by a deacetylase inhibitor reduces FBXL19 ubiquitination levels. Acetylation-mimic FBXL19 mutant exhibits a longer half-life than wild type. An acetyltransferase CBP catalyzes acetylation of FBXL19. Inhibition or down-regulation of CBP reduces FBXL19 stability, whereas it is increased in CBP-overexpressing cells. Taken together, the data indicate that CBP-mediated acetylation reduces ubiquitination and stabilizes FBXL19. Further, we demonstrate that FBXL19 targets small GTPase Cdc42 for its ubiquitination and degradation, whereas this effect is reversed by inhibition of CBP, suggesting that CBP increases the effect of SCF FBXL19 E3 ligase through acetylation and stabilization of FBXL19. Our study reveals a new molecular model for regulation of SCF E3 ligase function by acetylation and stabilization of its subunit F-box protein.-Wei, J., Dong, S., Yao, K., Martinez, M. F. Y. M., Fleisher, P. R., Zhao, Y., Ma, H., Zhao, J. Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F-box protein subunit.

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Section: Cbp Regulates Fbxl19 Acetylation and Stabilitymentioning

confidence: 99%

“…We have shown that CBP is a substrate of SCF FBXL19 E3 ligase (14). Overexpression of FBXL19 reduces CBP stability and mitigates CBP-mediated histone acetylation (14).…”

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confidence: 91%

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confidence: 99%

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Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

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“…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%

“…Since the original study on IU1, several groups have reported proteins that show accelerated degradation under IU1 treatment, including the Prion protein PrP [102,103], cGAS [108], phosphorylated tyrosine hydroxylase [104], the androgen receptor [105], vimentin [106], aurora kinase [111], CREB-binding protein [75], YFP-tagged CD3δ [107], and the model UPS substrate GFP u [107]. In many of these studies, the on-target nature of the IU1 effect is supported by genetic confirmation [102,105–108].…”

Section: Effects Of Deubiquitination On Substrate Degradationmentioning

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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SCF FBXW17 E3 ubiquitin ligase regulates FBXL19 stability and cell migration

Dong

Wei

Bowser

et al. 2020

J of Cellular Biochemistry

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The Skp1‐Cul1‐F‐box protein (SCF) E3 ligase complex is one of the largest ubiquitin E3 ligase families. FBXL19, a F‐box protein in SCFFBXL19 E3 ligase complex, regulates a variety of cellular responses including cell migration. We have shown that FBXL19 is not stable and its degradation is mediated by the ubiquitin–proteasome system, while the ubiquitin E3 ligase for FBXL19 ubiquitination and degradation has not been identified. In the study, we discovered that a new ubiquitin E3 ligase, SCFFBXW17, ubiquitinates and induces FBXL19 degradation. Exogenous FBXW17 targets FBXL19 for its ubiquitination and degradation. Lysine 114 in FBXL19 is a potential ubiquitin acceptor site. Acetylation of FBXL19 attenuated SCFFBXW17‐mediated FBXL19 degradation. SCFFBXL19 E3 ligase reduced Rac1 levels and cell migration, while the effects were attenuated by exogenous FBXW17. Downregulation of FBXW17 attenuated lysophosphatidic acid‐induced lamellipodia formation and Rac1 accumulation at migration leading edge. Taken together with our previous studies, FBXL19 is degraded by the ubiquitin–proteasome system and its site‐specific ubiquitination is mediated by SCFFBXW17 E3 ligase, which promotes cell migration.

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Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation

Cited by 34 publications

References 41 publications

Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

SCF FBXW17 E3 ubiquitin ligase regulates FBXL19 stability and cell migration

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