Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism
Anie P. Masilamani,
Rana Schulzki,
Shuai Yuan,
Ira V. Haase,
Eva Kling,
Franziska Dewes,
Geoffroy Andrieux,
Melanie Börries,
Oliver Schnell,
Dieter H. Heiland,
Oliver Schilling,
Roberto Ferrarese,
Maria S. Carro
Affiliations
Anie P. Masilamani
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Rana Schulzki
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Shuai Yuan
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Ira V. Haase
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Eva Kling
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Franziska Dewes
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Geoffroy Andrieux
Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany
Melanie Börries
Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany
Oliver Schnell
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Dieter H. Heiland
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany
Oliver Schilling
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany; Institute of Clinical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Roberto Ferrarese
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany
Maria S. Carro
Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany; Corresponding author
Summary: Proteolytic cleavage is an important post-translational mechanism to increase protein variability and functionality. In cancer, this process can be deregulated to shut off tumor-suppressive functions. Here, we report that in glioblastoma (GBM), the tumor suppressor ZBTB18 is targeted for protein cleavage by the intracellular protease calpain. The N-terminal (Nte) ZBTB18 cleaved fragment localizes to the cytoplasm and thus, is unable to exert the gene expression repressive function of the uncleaved protein. Mass spectrometry (MS) analysis indicates that the Nte ZBTB18 short form (SF) interacts with C-terminal (Cte) binding proteins 1 and 2 (CTBP1/2), which appear to be involved in HIF1A signaling activation. In fact, we show that the new ZBTB18 product activates HIF1A-regulated genes, which in turn lead to increased lipid uptake, lipid droplets (LD) accumulation, and enhanced metabolic activity. We propose that calpain-mediated ZBTB18 cleavage represents a new mechanism to counteract ZBTB18 tumor suppression and increase tumor-promoting functions in GBM cells.
