Subunit 3 of the COP9 Signalosome Is Poised to Facilitate Communication between the Extracellular Matrix and the Nucleus through the Muscle-Specific β1D Integrin

Hunter, Chris; Evans, Jennifer; Valencik, Maria L.

doi:10.1080/15419060802198660

Cited by 8 publications

(14 citation statements)

References 41 publications

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“…Historically, the CSN was defined as a nuclear complex (42,43), but more recent studies have demonstrated that CSN subunits are also localized in the cytoplasm (44)(45)(46)(47). To systematically dissect the subcellular distribution of the CSN complex, we generated stable HEK293 cell lines, expressing the fluorescent protein Cerulean (Cer), fused to the N terminus of subunit CSN2, CSN3, CSN5, CSN6, or CSN7 (48).…”

Section: Resultsmentioning

confidence: 99%

Dynamic Regulation of the COP9 Signalosome in Response to DNA Damage

Füzesi-Levi

Ben‐Nissan

Bianchi

et al. 2014

Molecular and Cellular Biology

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The COP9 signalosome (CSN) is an evolutionarily conserved protein complex that participates in the regulation of the ubiquitin/26S proteasome pathway by controlling the function of cullin-RING-ubiquitin ligases. Impressive progress has been made in deciphering its critical role in diverse cellular and developmental processes. However, little is known about the underlying regulatory principles that coordinate its function. Through biochemical and fluorescence microscopy analyses, we determined that the complex is localized in the cytoplasm, nucleoplasm, and chromatin-bound fractions, each differing in the composition of posttranslationally modified subunits, depending on its location within the cell. During the cell cycle, the segregation between subcellular localizations remains steady. However, upon UV damage, a dose-dependent temporal shuttling of the CSN complex into the nucleus was seen, accompanied by upregulation of specific phosphorylations within CSN1, CSN3, and CSN8. Taken together, our results suggest that the specific spatiotemporal composition of the CSN is highly controlled, enabling the complex to rapidly adapt and respond to DNA damage.

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Section: Resultsmentioning

confidence: 99%

Dynamic Regulation of the COP9 Signalosome in Response to DNA Damage

Füzesi-Levi

Ben‐Nissan

Bianchi

et al. 2014

Molecular and Cellular Biology

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“…In striated myocytes, integrins are localized to costameres at Z-discs where they contribute to the structural integrity of the muscle and are well positioned to sense mechanical stress generated by muscle contraction (3,14,28). At this site, integrin receptors link the ECM to the force generating actin-myosin cytoskeleton via a number of cytoplasmic proteins (35).…”

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confidence: 99%

Influence of the extracellular matrix and integrins on volume-sensitive osmolyte anion channels in C2C12 myoblasts

Neveux¹,

Doe

Leblanc

et al. 2010

American Journal of Physiology-Cell Physiology

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The purpose of this study was to determine whether extracellular matrix (ECM) composition through integrin receptors modulated the volume-sensitive osmolyte anion channels (VSOACs) in skeletal muscle-derived C2C12 cells. Cl(-) currents were recorded in whole cell voltage-clamped cells grown on laminin (LM), fibronectin (FN), or in the absence of a defined ECM (NM). Basal membrane currents recorded in isotonic media (300 mosmol/kg) were larger in cells grown on FN (3.8-fold at +100 mV) or LM (8.8-fold at +100 mV) when compared with NM. VSOAC currents activated by cell exposure to hypotonic solution were larger in cells grown on LM (1.72-fold at +100 mV) or FN (1.75-fold at +100 mV) compared with NM. Additionally, the kinetics of VSOAC activation was approximately 27% quicker on FN and LM. These currents were tamoxifen sensitive, displayed outward rectification, reversed at the equilibrium potential of Cl(-) and inactivated at potentials >+60 mV. Specific knockdown of beta(1)-integrin by short hairpin RNA interference strongly inhibited the VSOAC Cl(-) currents in cells plated on FN. In conclusion, ECM composition and integrins profoundly influence the biophysical properties and mechanisms of onset of VSOACs.

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“…Our previous work showed that CSN3 is a newly identified downstream effector of β1D integrin [19]. The β1D integrin isoform is only expressed in mature striated muscle, localizes to focal adhesions during muscle cell differentiation and its knockdown impairs myogenesis [19, 34, 35].…”

Section: Resultsmentioning

confidence: 99%

“…The β1D integrin isoform is only expressed in mature striated muscle, localizes to focal adhesions during muscle cell differentiation and its knockdown impairs myogenesis [19, 34, 35]. However, the role of CSN3 in skeletal muscle myogenesis remains unclear.…”

Section: Resultsmentioning

confidence: 99%

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Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway

Surina

Singer

et al. 2017

BMC Pharmacol Toxicol

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BackgroundThe COP9 signalosome (CSN) is a conserved protein complex composed of 8 subunits designated CSN1-CSN8. CSN3 represents the third subunit of the CSN and maintains the integrity of the complex. CSN3 binds to the striated muscle-specific β1D integrin tail, and its subcellular localization is altered in differentiated skeletal muscle cells. However, the role of CSN3 in skeletal muscle differentiation is unknown. The main goal of this study was to identify whether CSN3 participates in myoblast differentiation and the signalling mechanisms involved using C2C12 cells as a skeletal muscle cell model.MethodsSmall-hairpin (shRNA) was used to knockdown CSN3 in C2C12 cells. Differentiation was evaluated by immunostaining and confocal microscopy. Markers of differentiation, NF-κB signaling and CSN subunits expression, were assessed by immunoblotting and/or immunostaining. Cell proliferation was analysed by cell counting, flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Data were analyzed by one or two-way analysis of variance (ANOVA) followed by post-hoc testing.ResultsTransduction of C2C12 cells with two distinct CSN3 shRNAs led to the production of two cells lines expressing 7% of CSN3 protein (shCSN3-Low) and 43% of CSN3 protein (CSN3-Med) compared to controls. Knockdown of CSN3 was accompanied by destabilization of several CSN subunits and increased nuclear NF-κB localization. shCSN3-Med cells expressed less myogenin and formed shorter and thinner myotubes. In contrast, the shCSN3-Low cells expressed higher levels of myogenin prior and during the differentiation and remained mononucleated throughout the differentiation period. Both CSN3 knockdown cell lines failed to express sarcomeric myosin heavy chain (MHC) protein during differentiation. The fusion index was significantly higher in control cells than in shCSN3-Med cells, whereas shCSN3-Low cells showed no cell fusion. Interestingly, CSN3 knockdown cells exhibited a significantly slower growth rate relative to the control cells. Cell cycle analysis revealed that CSN3 knockdowns delayed in S phase and had increased levels of nuclear p21/Cip1 and p27/Kip1.ConclusionsThis study clarifies the first step toward unrevealing the CSN3/CSN-mediated pathways that controls C2C12 differentiation and proliferation. Further in vivo characterization of CSN/CSN3 may lead to the discovery of novel therapeutic target of skeletal muscle diseases such as muscular dystrophies.

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Subunit 3 of the COP9 Signalosome Is Poised to Facilitate Communication between the Extracellular Matrix and the Nucleus through the Muscle-Specific β1D Integrin

Cited by 8 publications

References 41 publications

Dynamic Regulation of the COP9 Signalosome in Response to DNA Damage

Dynamic Regulation of the COP9 Signalosome in Response to DNA Damage

Influence of the extracellular matrix and integrins on volume-sensitive osmolyte anion channels in C2C12 myoblasts

Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway

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