title: miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL.
abstract: Resistance toward CD95-mediated apoptosis is a hallmark of many different malignancies, as it is known from primary chronic lymphocytic leukemia (CLL) cells. Previously, we could show that miR-138 and -424 are downregulated in CLL cells. Here, we identified 2 new target genes, namely acyl protein thioesterase (APT) 1 and 2, which are under control of both miRs and thereby significantly overexpressed in CLL cells. APTs are the only enzymes known to promote depalmitoylation. Indeed, membrane proteins are significantly less palmitoylated in CLL cells compared with normal B cells. We identified APTs to directly interact with CD95 to promote depalmitoylation, thus impairing apoptosis mediated through CD95. Specific inhibition of APTs by siRNAs, treatment with miRs-138/-424, and pharmacologic approaches restore CD95-mediated apoptosis in CLL cells and other cancer cells, pointing to an important regulatory role of APTs in CD95 apoptosis. The identification of the depalmitoylation reaction of CD95 by APTs as a microRNA (miRNA) target provides a novel molecular mechanism for how malignant cells escape from CD95-mediated apoptosis. Here, we introduce palmitoylation as a novel posttranslational modification in CLL, which might impact on localization, mobility, and function of molecules, survival signaling, and migration.
authors: Department I of Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Valeska
authors: V
authors: Berg
authors: Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany;
authors: Marion
authors: M
authors: Rusch
authors: Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany;
authors: Nachiket
authors: N
authors: Vartak
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Christian
authors: C
authors: Jüngst
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Astrid
authors: A
authors: Schauss
authors: Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany; Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany;
authors: Herbert
authors: H
authors: Waldmann
authors: Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany;
authors: Christian
authors: C
authors: Hedberg
authors: Department I of Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Christian P
authors: CP
authors: Pallasch
authors: Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany; Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany; and.
authors: Philippe I H
authors: PI
authors: Bastiaens
authors: Department I of Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Michael
authors: M
authors: Hallek
authors: Department I of Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany.
authors: Clemens-Martin
authors: CM
authors: Wendtner
authors: Department I of Internal Medicine and Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
authors: Lukas P
authors: LP
authors: Frenzel
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D054878:Lipoylation; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C546110:MIRN138 microRNA, human; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D012333:RNA, Messenger; D019014:fas Receptor; D008156:Luciferases; C402226:LYPLA1 protein, human; C581317:LYPLA2 protein, human; D013869:Thiolester Hydrolases