The large GTPase Guanylate-Binding Protein-1 (GBP-1) promotes mitochondrial fission in glioblastoma

Abstract Glioblastomas (aka Glioblastoma multiforme (GBMs)) are the most deadly of the adult brain tumors. Even with aggressive treatment, the prognosis is extremely poor. The large GTPase Guanylate-Binding Protein-1 (GBP-1) contributes to the poor prognosis of GBM by promoting migration and invasion. GBP-1 is substantially localized to the cytosolic side of the outer membrane of mitochondria in GBM cells. Because mitochondrial dynamics, particularly mitochondrial fission, can drive cell migration and invasion, the potential interactions between GBP-1 and mitochondrial dynamin-related protein 1 (Drp1) were explored. Drp1 is the major driver of mitochondrial fission. While GBP-1 and Drp1 both had punctate distributions within the cytoplasm and localized to regions of the cytoplasmic side of the plasma membrane of GBM cells, the proteins were only molecularly co-localized at the mitochondria. Subcellular fractionation showed that the presence of elevated GBP-1 promoted the movement of Drp1 from the cytosol to the mitochondria. Migration of U251 cells treated with the Drp1 inhibitor, Mdivi-1, was less inhibited in the cells with elevated GBP-1. Elevated GBP-1 in GBM cells resulted in shorter and wider mitochondria, most likely from mitochondrial fission. Mitochondrial fission can drive a number of important cellular processes, including cell migration, invasion, and metastasis. Simple Summary Glioblastomas are the most common and most aggressive adult brain tumors arising from astrocytes. Up to 60% of glioblastomas are promoted by either amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR). The large GTPase Guanylate-Binding Protein-1 (GBP-1) is one of the most robustly induced proteins following EGFR signaling in glioblastomas. How GBP-1 promotes tumor progression in glioblastomas is still under investigation. This study shows that GBP-1 promotes tumor progression by associating with Drp1 at glioblastoma mitochondria and enhancing their fission. Specifically, increased mitochondrial fission can promote tumor cell migration, invasion, and metastasis.