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miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1
Valeska Berg1, Marion Rusch2, Nachiket Vartak3
1Department 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;
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.
Insights
Chronic lymphocytic leukemia (CLL) cells resist apoptosis by overexpressing acyl protein thioesterases (APTs) that depalmitoylate CD95. Inhibiting APTs restores CD95-mediated apoptosis in cancer cells.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Resistance to CD95-mediated apoptosis is a key feature of many cancers, including chronic lymphocytic leukemia (CLL).
- Previous studies showed miR-138 and miR-424 are downregulated in CLL cells.
- Acyl protein thioesterases (APTs) are enzymes involved in depalmitoylation.
Purpose of the Study:
- To identify novel molecular mechanisms by which CLL cells evade CD95-mediated apoptosis.
- To investigate the role of APTs and protein palmitoylation in CD95 regulation in CLL.
Main Methods:
- Target gene identification for downregulated miRs in CLL.
- Analysis of protein palmitoylation levels in CLL cells.
- Investigation of APTs' interaction with CD95.
- Experimental inhibition of APTs and miRNA treatment.
Main Results:
- APTs 1 and 2 were identified as direct targets of miR-138 and miR-424, and were overexpressed in CLL cells.
- CLL cells showed reduced palmitoylation of membrane proteins, including CD95.
- APTs directly interact with CD95, promoting its depalmitoylation and inhibiting CD95-mediated apoptosis.
- Inhibition of APTs or restoration of miRNA levels restored CD95-mediated apoptosis in CLL and other cancer cells.
Conclusions:
- APTs mediate the depalmitoylation of CD95, representing a novel mechanism for cancer cells to escape apoptosis.
- Palmitoylation is a newly identified posttranslational modification in CLL with potential roles in cell signaling and survival.
- Targeting APTs offers a potential therapeutic strategy to restore apoptosis in malignant cells.
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