CYLD, a deubiquitinase specific for lysine63-linked polyubiquitins, accumulates at the postsynaptic density in an activity-dependent manner

Döṡemeci, Ayṡe; Thein, Soe; Yang, Yijung; Reese, Thomas S.; Tao-Cheng, Jung-Hwa

doi:10.1016/j.bbrc.2012.10.131

Cited by 34 publications

(26 citation statements)

References 31 publications

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“…We have so far established that certain enzymes, a protein kinase CaMKII, a small G-protein regulator SynGAP and a deubiquitinase CYLD, redistribute in response to depolarization or NMDA application [8], [17], [16], [18], and that the movements of all three molecules are blocked upon inhibition of CaMKII [13], [10], [11]. …”

Section: Discussionmentioning

confidence: 99%

NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

Tao-Cheng

Yang

Bayer

et al. 2014

Biochemical and Biophysical Research Communications

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Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7–10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

Tao-Cheng

Yang

Bayer

et al. 2014

Biochemical and Biophysical Research Communications

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“…The PSD complex was defined as the postsynaptic specialization that comprises the electron dense PSD core and a network contiguous to it. The area of the PSD complex to be measured was outlined as described previously [9]. CYLD and p-CYLD labels appeared as individual black grains at the PSD complex, and immunolabeling intensity was expressed as the number of labels per μm length of the PSD.…”

Section: Methodsmentioning

confidence: 99%

“…Immuno electronmicroscopy (EM) on hippocampal cultures revealed that even though more CYLD accumulates at the PSD under excitatory conditions, the protein is also present at the synapse in the absence of stimulation, although at lower quantity [9]. We previously reported that CaMKII mediates NMDA-induced recruitment and activation of CYLD at the PSD [10], but the regulation of CYLD under basal conditions is still elusive.…”

Section: Introductionmentioning

confidence: 99%

IKK regulates the deubiquitinase CYLD at the postsynaptic density

Thein

Pham

Bayer

et al. 2014

Biochemical and Biophysical Research Communications

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K63-linked polyubiquitination of proteins regulates their trafficking into specific cellular pathways such as endocytosis and autophagy. CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is present in high quantities at the postsynaptic density (PSD). It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca2+-dependent manner. The observation that CYLD can also be phosphorylated in the absence of Ca2+ in isolated PSDs led us to further explore the regulation of CYLD under basal conditions. A possible involvement of the autonomous form CaMKII and IKK, both kinases known to be localized at the PSD, was examined. A CaMKII inhibitor CN21 had no effect on CYLD phosphorylation in the absence of Ca 2+, but two different IKK inhibitors, IKK16 and tatNEMO, inhibited its phosphorylation. Immuno electronmicroscopy on hippocampal cultures, using an antibody for CYLD phosphorylated at S-418, revealed that the phosphorylated form of CYLD is present at the PSD under basal conditions. Phosphorylation of CYLD under basal conditions was inhibited by IKK16. NMDA treatment further promoted phosphorylation of CYLD at the PSD, but IKK16 failed to block the NMDA-induced effect. In vitro experiments using purified proteins demonstrated direct phosphorylation and activation of CYLD by the beta catalytic subunit of IKK. Activation of IKK in isolated PSDs also promoted phosphorylation of CYLD and an increase in endogenous deubiquitinase activity specific for K63-linked polyubiquitins. Altogether, the results suggest that in the absence of excitatory conditions, constitutive IKK activity at the PSD regulates CYLD and maintains basal levels of K63-linkage specific deubiquitination at the synapse.

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“…Neuroscientific studies have indicated that CYLD accumulates in the postsynaptic density (PSD) and is thought to be involved in removing K-63 from PSD proteins, preventing their autophagic regulation [56]. This accumulation and lack of recycling may cause neurodegeneration [56].…”

Section: Cyld Overviewmentioning

confidence: 99%

CYLD-Mediated Signaling and Diseases

Mathis¹,

Lai²,

Qu³

et al. 2015

CDT

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The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NF-kB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

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CYLD, a deubiquitinase specific for lysine63-linked polyubiquitins, accumulates at the postsynaptic density in an activity-dependent manner

Cited by 34 publications

References 31 publications

NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

IKK regulates the deubiquitinase CYLD at the postsynaptic density

CYLD-Mediated Signaling and Diseases

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