TY - JOUR
T1 - Palmitoylation by DHHC5/8 Targets GRIP1 to Dendritic Endosomes to Regulate AMPA-R Trafficking
AU - Thomas, Gareth M.
AU - Hayashi, Takashi
AU - Chiu, Shu-Ling
AU - Chen, Chih Ming
AU - Huganir, Richard L.
N1 - Funding Information:
We gratefully acknowledge Drs. Masaki and Yuko Fukata (National Institutes of Natural Sciences, Okazaki, Japan) for mouse DHHC cDNAs, and Dr. Y. Igarashi (Hokkaido University, Japan) for human DHHC5 and DHHC8 cDNA. We thank Mrs. Min Dai for neuronal “Banker” cultures, Mr. R. Johnson for the myc-FUW vector and KBD construct, Mrs. L. Hamm for expert technical assistance, Dr. C.-Y. Su (Yale University) for comments on the manuscript, and Dr. V. Anggono and all other R.L.H. lab members for helpful discussions. This work was supported by funding from the Howard Hughes Medical Institute and the NIH (R01 MH64856). Under a licensing agreement between Millipore Corporation and The Johns Hopkins University, R.L.H. is entitled to a share of royalties received by the University on sales of products described in this article. R.L.H. is a paid consultant to Millipore Corporation. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
PY - 2012/2/9
Y1 - 2012/2/9
N2 - Palmitoylation, a key regulatory mechanism controlling protein targeting, is catalyzed by DHHC-family palmitoyl acyltransferases (PATs). Impaired PAT activity is linked to neurodevelopmental and neuropsychiatric disorders, suggesting critical roles for palmitoylation in neuronal function. However, few substrates for specific PATs are known, and functional consequences of palmitoylation events are frequently uncharacterized. Here, we identify the closely related PATs DHHC5 and DHHC8 as specific regulators of the PDZ domain protein GRIP1b. Binding, palmitoylation, and dendritic targeting of GRIP1b require a PDZ ligand unique to DHHC5/8. Palmitoylated GRIP1b is targeted to trafficking endosomes and may link endosomes to kinesin motors. Consistent with this trafficking role, GRIP1b's palmitoylation turnover rate approaches the highest of all reported proteins, and palmitoylation increases GRIP1b's ability to accelerate AMPA-R recycling. To our knowledge, these findings identify the first neuronal DHHC5/8 substrate, define novel mechanisms controlling palmitoylation specificity, and suggest further links between dysregulated palmitoylation and neuropathological conditions.
AB - Palmitoylation, a key regulatory mechanism controlling protein targeting, is catalyzed by DHHC-family palmitoyl acyltransferases (PATs). Impaired PAT activity is linked to neurodevelopmental and neuropsychiatric disorders, suggesting critical roles for palmitoylation in neuronal function. However, few substrates for specific PATs are known, and functional consequences of palmitoylation events are frequently uncharacterized. Here, we identify the closely related PATs DHHC5 and DHHC8 as specific regulators of the PDZ domain protein GRIP1b. Binding, palmitoylation, and dendritic targeting of GRIP1b require a PDZ ligand unique to DHHC5/8. Palmitoylated GRIP1b is targeted to trafficking endosomes and may link endosomes to kinesin motors. Consistent with this trafficking role, GRIP1b's palmitoylation turnover rate approaches the highest of all reported proteins, and palmitoylation increases GRIP1b's ability to accelerate AMPA-R recycling. To our knowledge, these findings identify the first neuronal DHHC5/8 substrate, define novel mechanisms controlling palmitoylation specificity, and suggest further links between dysregulated palmitoylation and neuropathological conditions.
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U2 - 10.1016/j.neuron.2011.11.021
DO - 10.1016/j.neuron.2011.11.021
M3 - Article
C2 - 22325201
AN - SCOPUS:84863012668
SN - 0896-6273
VL - 73
SP - 482
EP - 496
JO - Neuron
JF - Neuron
IS - 3
ER -