TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO–IKK supramolecular structures

Tarantino, Nadine; Tinévez, Jean-Yves; Crowell, Elizabeth; Boisson, Bertrand; Henriques, Ricardo; Mhlanga, Musa M.; Agou, Fabrice; Israël, Alain; Laplantine, Emmanuel

doi:10.1083/jcb.201307172

Cited by 459 publications

(456 citation statements)

References 43 publications

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“…NF-κB is a ubiquitously expressed transcription factor involved in the regulation of inflammatory mediators associated with OA [42,43]. According to previous studies [44], IL-1β stimulation triggers the phosphorylation of the catalytic subunits of IKK (IKKα and IKKβ), as well as the binding protein of p65 (IκBα), which consequently frees p65 and translocates it from the cytosol to the nucleus and leads to the production of catabolic enzymes, cytokines, and inflammatory mediators. Additionally, LIG inhibits inflammation in macrophages via NF-κB inhibition.…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Ligustilide in Osteoarthritis: An in Vitro and in Vivo Study

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoarthritis is a degenerative joint disease characterized by cartilage degeneration and a chondrocyte inflammatory response that induces an inflammatory environment closely linked to extracellular matrix (ECM) degradation. Ligustilide (LIG) is a major component of the herb Radix Angelicae Sinensis, with demonstrated anti-inflammatory effects. To confirm whether LIG has an equally inhibitory effect on inflammation in human osteoarthritis chondrocytes, we performed in vivo and in vitro experiments to validate the above conjectures and determine the relevant mechanisms. Methods: Quantitative realtime PCR and western blotting were performed to evaluate the expression of MMP-3, MMP-13, ADAMTS-5, iNOS, and COX-2 at both gene and protein levels. An enzyme-linked immunosorbent assay was used to evaluate the levels of other inflammatory factors (PGE2, TNF-α, and IL-6). The PI3K/AKT and nuclear factor kappa B (NF-κB) signaling pathways were also analyzed by western blotting, whereas immunofluorescence was used to assess the expression of collagen II and aggrecan. The in vitro effect of LIG was evaluated by intraperitoneal injection into a mouse osteoarthritis model induced by destabilization of the medial meniscus. Results: LIG lowered the phosphorylation levels of p65, IκBα, and IKKα/β and suppressed the IL-1β-induced expression of MMP-3, ADAMTS-5, iNOS, and COX-2 and the inflammatory factors PGE2, TNF-α, and IL-6. LIG markedly decreased IL-1β-induced degradation of collagen II and aggrecan. In vivo results showed that LIG-treated mouse cartilage showed less damage than the control group; the Osteoarthritis Research Society International (OARSI) score was also lower. LIG further reduced the thickness of the subchondral bone plate and alleviated the synovitis. Conclusion: LIG may act as a promising therapeutic agent for osteoarthritis by attenuating IL-1β-induced inflammation in chondrocytes and ECM degradation via suppression of NF-κB activation by the PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 99%

The Protective Effect of Ligustilide in Osteoarthritis: An in Vitro and in Vivo Study

et al. 2018

Cell Physiol Biochem

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“…mediated by the exposure of a hydrophobic membrane insertion loop (36). Whole cell experiments have provided evidence that polyubiquitin may have a role in localizing NEMO to the plasma membrane (37)(38)(39), without the involvement of microtubules or actin (39). To investigate the potential for NEMO binding to the membrane environment, we performed a simple liposome binding assay.…”

Section: Tablementioning

confidence: 99%

Polyubiquitin Drives the Molecular Interactions of the NF-κB Essential Modulator (NEMO) by Allosteric Regulation

Catici¹,

Horne²,

Cooper

et al. 2015

Journal of Biological Chemistry

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Background: NF-B essential modulator (NEMO) is the key regulator of NF-B signaling, but how it performs this regulation is poorly understood. Results: NEMO is a highly flexible protein that shows ligand-specific conformational change. Conclusion: Unanchored polyubiquitin binding controls NEMO conformational state and functional activity. Significance: Our findings provide a detailed mechanistic understanding of NEMO activity and develop the non-degradative role of free polyubiquitin.

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“…S3 and S4, and Movies S1 and S2, time series were denoised as described (57). However, all data analysis was performed on the raw, unprocessed data as described (58,59). Full details of image, data, and statistical analysis are described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons

Gopal

Nirschl

Klinman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

229

247

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Ribonucleoprotein (RNP) granules are enriched in specific RNAs and RNA-binding proteins (RBPs) and mediate critical cellular processes. Purified RBPs form liquid droplets in vitro through liquid-liquid phase separation and liquid-like non-membrane-bound structures in cells. Mutations in the human RBPs TAR-DNA binding protein 43 and RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), but the biophysical properties of these proteins have not yet been studied in neurons. Here, we show that TDP-43 RNP granules in axons of rodent primary cortical neurons display liquid-like properties, including fusion with rapid relaxation to circular shape, shear stress-induced deformation, and rapid fluorescence recovery after photobleaching. RNP granules formed from wild-type TDP-43 show distinct biophysical properties depending on axonal location, suggesting maturation to a more stabilized structure is dependent on subcellular context, including local density and aging. Superresolution microscopy demonstrates that the stabilized population of TDP-43 RNP granules in the proximal axon is less circular and shows spiculated edges, whereas more distal granules are both more spherical and more dynamic. RNP granules formed by ALS-linked mutant TDP-43 are more viscous and exhibit disrupted transport dynamics. We propose these altered properties may confer toxic gain of function and reflect differential propensity for pathological transformation.TDP-43 | ribonucleoprotein granules | liquid droplets | amyotrophic lateral sclerosis | neurons C ellular organelles allow eukaryotic cells to organize biochemical processes and concentrate specific cellular reactions in space and time. Although the role of membrane-bound organelles in cytoplasmic compartmentalization has long been recognized, the distinct biophysical properties and functions of non-membrane-bound organelles enriched in RNA and proteins have been recognized only recently (1-5). Ribonucleoprotein (RNP) granules, such as P granules in Caenorhabditis elegans (1), nucleoli in Xenopus laevis oocytes (2), yeast P bodies (3), and mammalian stress granules (6), show liquid droplet properties (reviewed in refs. 5, 7, 8), including fusion with rapid relaxation to a spherical shape, dynamic internal rearrangements, and rapid dissolution and assembly. Proteins comprising RNP granules share a common structure containing both RNA recognition motifs (RRMs) and low-complexity sequences (LCSs), intrinsically disordered regions that mediate protein-protein interactions (7, 9). In vitro characterization of human RNP granule proteins, RNA-binding protein FUS and heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which are mutated in rare inherited forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (10-12), has revealed the LCS drives self-assembly of RNP granules through a process termed liquid-liquid phase separation (LLPS) (6, 13-18).Among eukaryotic cells, neurons face unique challenges in spatiotemporal cytoplasmic organization related to their com...

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TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO–IKK supramolecular structures

Abstract: The mechanism of NEMO recruitment into supramolecular complexes and its dependence on ubiquitination differs in response to the proinflammatory cytokines TNF and IL-1.

Cited by 459 publications

References 43 publications

The Protective Effect of Ligustilide in Osteoarthritis: An in Vitro and in Vivo Study

The Protective Effect of Ligustilide in Osteoarthritis: An in Vitro and in Vivo Study

Polyubiquitin Drives the Molecular Interactions of the NF-κB Essential Modulator (NEMO) by Allosteric Regulation

Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons

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