title: Palmitoyl acyltransferase zD17 mediates neuronal responses in acute ischemic brain injury by regulating JNK activation in a signaling module.
abstract: 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.
authors.affiliation: Brain Research Centre, Vancouver, British Columbia, Canada. photonyg@interchange.ubc.ca
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Max S
authors.initials: MS
authors.lastname: Cynader
mesh_terms: D000217:Acyltransferases / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001930:Brain Injuries / Q000201:enzymology* / Q000517:prevention & control; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000217:Acyltransferases; C473038:ZDHHC17 protein, human; D048031:JNK Mitogen-Activated Protein Kinases