title: CaMKII mediates recruitment and activation of the deubiquitinase CYLD at the postsynaptic density.
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.
authors.affiliation: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Soe
authors.initials: S
authors.lastname: Thein
authors.affiliation: EM Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Tao-Cheng
authors.affiliation: Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
authors.affiliation: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reese
authors.affiliation: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ayse
authors.initials: A
authors.lastname: Dosemeci
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000648:ultrastructure; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D025821:Polyubiquitin / Q000378:metabolism; D057907:Post-Synaptic Density / Q000201:enzymology*; D021381:Protein Transport / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000737:chemistry / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D016202:N-Methylaspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D064570:Ubiquitin-Specific Proteases; D008239:Lysine