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Sci. Signal., 9 July 2013
Vol. 6, Issue 283, p. ra57
[DOI: 10.1126/scisignal.2003727]


JNK3 Couples the Neuronal Stress Response to Inhibition of Secretory Trafficking

Guang Yang1*, Xun Zhou1, Jingyan Zhu2, Rui Liu1, Si Zhang1, Ainsley Coquinco1, Yongting Chen1, Yanhua Wen1, Luba Kojic1, William Jia1,2, and Max S. Cynader1*

1 Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada.
2 Department of Surgery, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

Abstract: Secretory trafficking through the Golgi complex is critical for neuronal development, function, and stress response. Altered secretion is associated with the pathogenesis of various neurological diseases. We found that c-Jun amino-terminal kinase 3 (JNK3) inhibited secretory trafficking by promoting the depletion of phosphatidylinositol 4-phosphate (PI4P) in the Golgi complex of COS7 cells and primary rat neurons. Exposure of cultured primary rat neurons to excitotoxic concentrations of NMDA (N-methyl-D-aspartate), an agonist of a class of ionotropic glutamate receptors, or overexpression of zD17 (a palmitoyl transferase) resulted in JNK3 palmitoylation and association with the Golgi complex. Analysis of mutant constructs of JNK3 indicated that Golgi association was independent of its kinase activity but depended on its palmitoylation. The association of JNK3 with the Golgi in cultured neurons decreased the secretory trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 (glutamate receptor subunit 1), a component of ionotropic glutamate receptors found at glutamatergic synapses. Palmitoylated JNK3 bound to the phosphatase Sac1, increasing its abundance at the Golgi and thereby decreasing the abundance of PI4P, a lipid necessary for post-Golgi trafficking. Disrupting the JNK3-Sac1 interaction with two synthetic peptides prevented the loss of surface GluR1 and preserved synaptic integrity in cultured neurons exposed to NMDA. Together, our results suggest that JNK3 participates in an adaptive response to neuronal hyperexcitation by impeding secretory trafficking at the Golgi complex.

* Corresponding author. E-mail: cynader{at} (M.S.C.); photonyg{at} (G.Y.)

Citation: G. Yang, X. Zhou, J. Zhu, R. Liu, S. Zhang, A. Coquinco, Y. Chen, Y. Wen, L. Kojic, W. Jia, M. S. Cynader, JNK3 Couples the Neuronal Stress Response to Inhibition of Secretory Trafficking. Sci. Signal. 6, ra57 (2013).

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