GC1qR Cleavage by Caspase-1 Drives Aerobic Glycolysis in Tumor Cells

Annika Sünderhauf; Annika Raschdorf; Maren Hicken; Heidi Schlichting; Franziska Fetzer; Ann-Kathrin Brethack; Sven Perner; Claudia Kemper; Berhane Ghebrehiwet; Christian Sina; Stefanie Derer

doi:10.3389/fonc.2020.575854

GC1qR Cleavage by Caspase-1 Drives Aerobic Glycolysis in Tumor Cells

Front Oncol. 2020 Sep 30:10:575854. doi: 10.3389/fonc.2020.575854. eCollection 2020.

Authors

Affiliations

¹ Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany.
² Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, Germany.
³ Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
⁴ Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States.
⁵ Faculty of Life Sciences and Medicine, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.
⁶ Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
⁷ Department of Medicine, Stony Brook University, Stony Brook, NY, United States.
⁸ 1st Department of Medicine, Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany.

Abstract

Self-sustained cell proliferation constitutes one hallmark of cancer enabled by aerobic glycolysis which is characterized by imbalanced glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) activity, named the Warburg effect. The C1q binding protein (C1QBP; gC1qR) is pivotal for mitochondrial protein translation and thus OXPHOS activity. Due to its fundamental role in balancing OXPHOS and glycolysis, c1qbp ^-/- mice display embryonic lethality, while gC1qR is excessively up-regulated in cancer. Although gC1qR encompasses an N-terminal mitochondrial leader it is also located in other cellular compartments. Hence, we aimed to investigate mechanisms regulating gC1qR cellular localization and its impact on tumor cell metabolism. We identified two caspase-1 cleavage sites in human gC1qR. GC1qR cleavage by active caspase-1 was unraveled as a cellular mechanism that prevents mitochondrial gC1qR import, thereby enabling aerobic glycolysis and enhanced cell proliferation. Ex vivo, tumor grading correlated with non-mitochondrial-located gC1qR as well as with caspase-1 activation in colorectal carcinoma patients. Together, active caspase-1 cleaves gC1qR and boosts aerobic glycolysis in tumor cells.

Keywords: C1qbp; OXPHOS; aerobic glycolysis; caspase-1; gC1qR; inflammasome; mitochondria; p32/HABP1.