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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.

SUBMITTER: Yang G

PROVIDER: S-EPMC6623198 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Palmitoyl acyltransferase zD17 mediates neuronal responses in acute ischemic brain injury by regulating JNK activation in a signaling module.

Yang Guang G Cynader Max S MS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110801 33

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 ind ...[more]

PMID: 21849558

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Project description:Acute kidney injury (AKI) is associated with an abrupt loss of kidney function that results in significant morbidity and mortality. Considerable effort has focused around the identification of diagnostic biomarkers and the analysis of molecular events. Most studies have adopted organ-wide approaches that do not fully capture the interplay among different cell types in the pathophysiology of AKI. To extend our understanding of molecular and cellular events in AKI, we developed a mouse line that enables the identification of translational profiles in specific cell types by CRE recombinase-dependent activation of an eGFP-tagged L10a ribosomal protein subunit, and consequently, translating ribosome affinity purification (TRAP) of mRNA populations. By utilizing cell-type specific CRE-driver lines, in this study we identify distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Cell-specific translational expression profiles were uncovered 24 hours after IRI from four populations enriched for distinct anatomical and cellular subgroups: nephron, interstitial cell populations, vascular endothelium, and macrophages/monocytes by Affymetrix microarray. A construct containing the CAGGS promoter driving eGFP-L10a, with a loxP-site flanked triple SV40 polyA cassette between promoter and eGFP-L10a cassette was targeted into the ubiquitously active Rosa26 locus. The upstream polyA cassette is designed to block activity of the downstream eGFP-L10a cassette. CRE-dependent removal of this transcriptional block activates eGFP::L10a production within the CRE-producing cell, and all of its descendants. Mice carrying the conditional eGFP-L10a allele, referred to as L10a, were maintained in a homozygous state. L10a mice were crossed to four CRE strains to activate eGFP::L10a expression in four predominantly non-overlapping cellular compartments in the kidney. A Six2-Tet-GFP::CRE allele is active exclusively within nephron progenitors; consequently, historical labeling results in eGFP::L10a expression throughout the main body of the nephron. A Foxd1-GFP::CRE allele is active in the progenitors of many of the interstitial cell lineages including those generating mesangial and non-glomerular pericytes. In addition, Foxd1 is normally expressed in podocytes. Cdh5-CRE is reported to be active throughout the vascular endothelium, and finally, Lyz2-CRE specifically labels cells of the myeloid lineage, notably macrophages, monocytes and dendritic cells. Mice carrying any CRE allele and the L10a allele are designated generically CRE-L10a. six2-L10a, foxd1-L10a, cdh5-L10a and lyz2-L10a denote specifically mice that are compound heterozygotes for the indicated CRE driver and L10a. CRE-L10a, L10a heterozygous littermates without CRE allele, C57BL/6 wild type mice were subjected to renal bilateral warm ischemia 28 minutes followed by 24-hour reperfusion when the kidney TRAP RNA and total RNA were isolated and subjected to Affymetrix microarray. Biological triplicates for each CRE-L10a line underwent no Surgery; sham Surgery and IRI treatment.

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Palmitoyl acyltransferase zD17 mediates neuronal responses in acute ischemic brain injury by regulating JNK activation in a signaling module.

Publications

Palmitoyl acyltransferase zD17 mediates neuronal responses in acute ischemic brain injury by regulating JNK activation in a signaling module.

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