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

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 cle...

Full description

Saved in:
Bibliographic Details
Published iniScience Vol. 25; no. 7; p. 104625
Main Authors Masilamani, Anie P., Schulzki, Rana, Yuan, Shuai, Haase, Ira V., Kling, Eva, Dewes, Franziska, Andrieux, Geoffroy, Börries, Melanie, Schnell, Oliver, Heiland, Dieter H., Schilling, Oliver, Ferrarese, Roberto, Carro, Maria S.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 15.07.2022
Elsevier
Subjects
Biochemistry
Cancer
Molecular biology
Transcriptomics
Biochemistry
Molecular biology
Transcriptomics
Cancer
Online AccessGet full text

Cover

More Information
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. [Display omitted] •Calpain mediates ZBTB18 cleavage in GBM cells•ZBTB18 SF-Nte localizes in the cytoplasm and interacts with CTBP1/2•ZBTB18 SF-Nte regulates the expression of HIF targets•ZBTB18 SF-Nte regulates lipid uptake Biochemistry; Molecular biology; Cancer; Transcriptomics
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Present address: School of Medicine, Henan Polytechnic University, Henan, China
These authors contributed equally
Lead contact
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.104625