Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism

Masilamani AP, Schulzki R, Yuan S, Haase IV, Kling E, Dewes F, Andrieux G, Börries M, Schnell O, Heiland DH, Schilling O, Ferrarese R, Carro MS (2022)

Publication Type: Journal article

Publication year: 2022

Journal

iScience Elsevier

Book Volume: 25

Article Number: 104625

Journal Issue: 7

DOI: 10.1016/j.isci.2022.104625

Abstract

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.

Authors with CRIS profile

Oliver Schnell
Dieter Henrik Heiland

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Masilamani, A.P., Schulzki, R., Yuan, S., Haase, I.V., Kling, E., Dewes, F.,... Carro, M.S. (2022). Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism. iScience, 25(7). https://doi.org/10.1016/j.isci.2022.104625

MLA:

Masilamani, Anie P., et al. "Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism." iScience 25.7 (2022).

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