Palmitoylation Controls Death Receptor Function in Chronic Lymphocytic Leukemia

Abstract 2829 Introduction: Post-translational modifications are important fine-tuning elements for controlling protein activity and signaling. Palmitoylation is a common post-translational modification and defined as the addition of palmitic acid to internal cysteins. Interestingly, in contrast to other lipid modifications, it is reversible. Control over the palmitoylation cycle therefore provides indirect control over protein localization and function. While a number of proteins with palmitoyl transferase activity are known, LYPLA1 (lysophospholipase 1) is the only enzyme known to be responsible for the process of depalmitoylation. CLL cells are known to be resistant to TRAIL-mediated apoptosis. While TRAIL-R1 is reported to be palmitoylated, TRAIL-R2 seems to contain a region with basic amino acids in its membrane-proximal cytoplasmatic domain . Some studies showed that palmitoylation is crucial for several steps of death receptor signaling. Therefore, regulation of depalmitoylation by LYPLA1 seems to be an important tool for the regulation of death receptor function. Methods and Results: Global palmitoylation in CLL cells was investigated by screening for all palmitoylated proteins via a click chemistry assay. There, cells were metabolically labeled, coupled to a specific reporter group and then analyzed by in-gel fluorescence. Comparison of healthy B cells, healthy PBMCs and CLL cells revealed a significant difference in global palmitoylation (+38.5 % in B cells, n=6, p Conclusion: We show for the first time, that LYPLA1 is a central enzyme which regulates the apoptotic signaling of TRAIL. Furthermore, we identified LYPLA1 to be regulated by miRNAs, which are deregulated in CLL. These novel findings allow speculation, that LYPLA1 inhibitors could be used for the treatment of CLL. Future experiments should therefore aim at investigating the LYPLA1 signaling pathway as a potential target for CLL/ cancer therapy. L.P.F. and V.F. contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.