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Published online
doi:10.1083/jcb.200903101
The Journal of Cell Biology, Vol. 186, No. 1, 147-160
The Rockefeller University Press, 0021-9525 $30.00
© Noritake et al.
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Article

Mobile DHHC palmitoylating enzyme mediates activity-sensitive synaptic targeting of PSD-95



Jun Noritake1, Yuko Fukata1,2, Tsuyoshi Iwanaga1, Naoki Hosomi3, Ryouhei Tsutsumi1, Naoto Matsuda1, Hideki Tani4, Hiroko Iwanari3, Yasuhiro Mochizuki3, Tatsuhiko Kodama3, Yoshiharu Matsuura4, David S. Bredt5, Takao Hamakubo3, and Masaki Fukata1,2

1 Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8787, Japan
2 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan
3 Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan
4 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
5 Department of Neuroscience, Eli Lilly and Company, Indianapolis, IN 46285

Correspondence to Masaki Fukata: mfukata{at}nips.ac.jp

Protein palmitoylation is the most common posttranslational lipid modification; its reversibility mediates protein shuttling between intracellular compartments. A large family of DHHC (Asp-His-His-Cys) proteins has emerged as protein palmitoyl acyltransferases (PATs). However, mechanisms that regulate these PATs in a physiological context remain unknown. In this study, we efficiently monitored the dynamic palmitate cycling on synaptic scaffold PSD-95. We found that blocking synaptic activity rapidly induces PSD-95 palmitoylation and mediates synaptic clustering of PSD-95 and associated AMPA ({alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors. A dendritically localized DHHC2 but not the Golgi-resident DHHC3 mediates this activity-sensitive palmitoylation. Upon activity blockade, DHHC2 translocates to the postsynaptic density to transduce this effect. These data demonstrate that individual DHHC members are differentially regulated and that dynamic recruitment of protein palmitoylation machinery enables compartmentalized regulation of protein trafficking in response to extracellular signals.

Abbreviations used in this paper: 2-BP, 2-bromopalmitate; ABE, acyl-biotin exchange; AMPAR, AMPA receptor; βME, β-mercaptoethanol; CCD, charge-coupled device; CHX, cycloheximide; CM, chloroform-methanol; DIV, day in vitro; DN, dominant-negative; Kyn, kynurenic acid; LB, lysis buffer; miRNA, microRNA; NEM, N-ethyl-maleimide; NMDA, N-methyl-D-aspartate; PAT, palmitoyl acyltransferase; PPT, palmitoyl protein thioesterase; TARP, transmembrane AMPAR regulatory protein; TIRFM, total internal reflection fluorescence microscopy; TTX, tetrodotoxin; WT, wild type.

© 2009 Noritake et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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