Abstract
NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy. Recruitment of CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is blocked by pre-treatment with tatCN21, a CaMKII inhibitor, at a concentration that inhibits the translocation of CaMKII to the PSD. Furthermore, CaMKII co-immunoprecipitates with CYLD from solubilized PSD fractions, indicating an association between the proteins. Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. Activation of CaMKII in isolated PSDs promotes phosphorylation of CYLD on the same residues and also enhances endogenous deubiquitinase activity specific for K63-linked polyubiquitins. Since K63-linked polyubiquitin conjugation to proteins inhibits their interaction with proteasomes, CaMKII-mediated recruitment and upregulation of CYLD is expected to remove K63-linked polyubiquitins and facilitate proteasomal degradation at the PSD.
Highlights
Recruitment and activation of CaMKII produces several activity-induced changes at synapses [1]
These results suggest that similar to CaMKII [28], CYLD is recruited to the postsynaptic density (PSD) in response to Nmethyl-D-aspartic acid (NMDA) receptor activation
TatCN21, a cellpenetrating CaMKII inhibitor, at 20 mM blocked both CaMKII and CYLD accumulation at the PSD induced by NMDA (Fig. 1 A, c vs. b for CYLD and g vs. f for CaMKII, respectively)
Summary
Recruitment and activation of CaMKII produces several activity-induced changes at synapses [1]. CaMKII mediates these changes through a diverse set of downstream mechanisms, including, direct phosphorylation and upregulation of AMPA receptors [2], [3], anchoring of AMPA receptor to the postsynaptic density (PSD) via phosphorylation of TARPs, the adaptor proteins [4], [5], and regulation of the localization and activity of SynGAP through phosphorylation [6], [7]. Recent addition to this growing list is CaMKII-mediated recruitment and activation of proteasomes into spines [8], [9]. The type and degree of protein ubiquitination are regulated by ubiquitin ligases that conjugate ubiquitins and deubiquitinases leading to their removal
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