Repression of classical nuclear export by S-nitrosylation of CRM1

Wang, Peng; Liu, Guanghui; Wu, Kaiyuan; Qu, Jing; Huang, Bo; Zhang, Xu; Zhou, Xixi; Gerace, Larry; Chen, Chang

doi:10.1242/jcs.057026

Cited by 48 publications

(42 citation statements)

References 57 publications

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“…5B). These mutants in NES-binding site of CRM1 have been reported to abolish CRM1-NES association and abrogate export of classical NES sequences fused to GFP [41]. Our study both contributes to and validates the list of proteins known to be retinoylated (Table 1).…”

Section: Resultssupporting

confidence: 68%

Nuclear MEK1 Sequesters PPARγ and Bisects MEK1/ERK Signaling: A Non-Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation

et al. 2014

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Uncontrolled adipogenesis and adipocyte proliferation have been connected to human comorbidities. Retinoic acid (RA) is known to inhibit adipocyte differentiation, however the underlying mechanisms have not been adequately understood. This study reports that RA acting as a ligand to RA receptors (RARs and RXRs) is not a sine qua non to the inhibition of adipogenesis. Our intriguing observation of a negative correlation between increased retinoylation and adipogenesis led us to explore retinoylated proteins in adipocytes. Exportin (CRM1) was found to be retinoylated, which in turn can affect the spatio-temporal regulation of the important signaling molecule mitogen-activated protein kinase kinase 1 (MEK1), likely by disrupting its export from the nucleus. Nuclear enrichment of MEK1 physically sequesters peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis, from its target genes and thus inhibits adipogenesis while also disrupting the MEK1-extracellular-signal regulated kinase (ERK) signaling cascade. This study is first to report the inhibition of adipocyte differentiation by retinoylation.

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Section: Resultssupporting

confidence: 68%

Nuclear MEK1 Sequesters PPARγ and Bisects MEK1/ERK Signaling: A Non-Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation

et al. 2014

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“…Very recently, a similar function has been described for S-nitrosylation of CRM1 (29). Like LMB, 15d-PGJ 2 targets Cys-528 of CRM1.…”

mentioning

confidence: 63%

The Anti-inflammatory Prostaglandin 15-Deoxy-Δ12,14-PGJ2 Inhibits CRM1-dependent Nuclear Protein Export

Hilliard

Frohnert

Spillner

et al. 2010

Journal of Biological Chemistry

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The signaling molecule 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) has been described as the "anti-inflammatory prostaglandin." Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ 2 , identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ 2 reacts with a conserved cysteine residue in the CRM1 sequence. This covalent modification prevents the formation of nuclear export complexes. Cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of LMB and 15d-PGJ 2 , demonstrating that the same single amino acid is targeted by the two compounds. Inhibition of the CRM1 pathway by endogenously produced prostaglandin and/or exogenously applied 15d-PGJ 2 may contribute to its anti-inflammatory, anti-proliferative, and anti-viral effects.

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“…For example, redox-triggered reversible S-thiolation of transcription factor c-JUN regulates DNA binding (130). Snitrosylation of karyopherin chromosomal region maintenance 1 (the major receptor for classical nuclear protein export) inhibits its interaction with nuclear export signals and blocks protein export from the nucleus (333). The human p53 tumor suppressor is inhibited by S-glutathionylation both in vitro and in human cancer cells as a result of oxidative stress (323).…”

Section: Redox Signaling Through Protein Sulfhydryl Groupsmentioning

confidence: 99%

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

Rojo

McBean²,

Cindrić³

et al. 2014

Antioxidants & Redox Signaling

267

242

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Neurodegenerative diseases are characterized by chronic microglial over-activation and oxidative stress. It is now beginning to be recognized that reactive oxygen species (ROS) produced by either microglia or the surrounding environment not only impact neurons but also modulate microglial activity. In this review, we first analyze the hallmarks of pro-inflammatory and anti-inflammatory phenotypes of microglia and their regulation by ROS. Then, we consider the production of reactive oxygen and nitrogen species by NADPH oxidases and nitric oxide synthases and the new findings that also indicate an essential role of glutathione (c-glutamyl-lcysteinylglycine) in redox homeostasis of microglia. The effect of oxidant modification of macromolecules on signaling is analyzed at the level of oxidized lipid by-products and sulfhydryl modification of microglial proteins. Redox signaling has a profound impact on two transcription factors that modulate microglial fate, nuclear factor kappa-light-chain-enhancer of activated B cells, and nuclear factor (erythroid-derived 2)-like 2, master regulators of the pro-inflammatory and antioxidant responses of microglia, respectively. The relevance of these proteins in the modulation of microglial activity and the interplay between them will be evaluated. Finally, the relevance of ROS in altering blood brain barrier permeability is discussed. Recent examples of the importance of these findings in the onset or progression of neurodegenerative diseases are also discussed. This review should provide a profound insight into the role of redox homeostasis in microglial activity and help in the identification of new promising targets to control neuroinflammation through redox control of the brain.

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Repression of classical nuclear export by S-nitrosylation of CRM1

Cited by 48 publications

References 57 publications

Nuclear MEK1 Sequesters PPARγ and Bisects MEK1/ERK Signaling: A Non-Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation

Nuclear MEK1 Sequesters PPARγ and Bisects MEK1/ERK Signaling: A Non-Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation

The Anti-inflammatory Prostaglandin 15-Deoxy-Δ12,14-PGJ2 Inhibits CRM1-dependent Nuclear Protein Export

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

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