RT Journal Article SR Electronic T1 Palmitoyl Acyltransferase zD17 Mediates Neuronal Responses in Acute Ischemic Brain Injury by Regulating JNK Activation in a Signaling Module JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 11980 OP 11991 DO 10.1523/JNEUROSCI.2510-11.2011 VO 31 IS 33 A1 Guang Yang A1 Max S. Cynader YR 2011 UL http://www.jneurosci.org/content/31/33/11980.abstract AB Although the palmitoyl acyltransferase (PAT) zinc-finger DHHC containing 17 (zD17) has been implicated in genetic neurological disorders by regulating protein palmitoylation, the role of zD17 in acute brain injury remains unknown. Here, we report that zD17 contributes to acute ischemic brain injury via a mechanism independent of its PAT activity. We have found that zD17 directly interacts with c-Jun N terminus kinase (JNK) to form a signaling module for JNK activation. Pathological stressors induce the zD17–JNK interaction, which promotes downstream neuronal cell death signals. We have developed novel peptides targeting the JNK-interacting motif on zD17 to selectively block the enhancement of the zD17–JNK interaction and the activation of JNK isoforms 2 and 3. Application of these peptides successfully blocks JNK activation and neuronal cell death pathways, protects cultured neurons from excitotoxicity, and dramatically reduces brain damage and behavioral deficits in a rat model of focal ischemic stroke. Our findings indicate zD17 as a key player in ischemic stroke and suggest the potential therapeutic value of targeting the zD17–JNK interaction for acute brain injury.