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Loss of membrane remodeling BAR protein endophilin B1 is seen in many different forms of cancer and is highly correlated with dysregulation in the pathways that control cell fate, specifically autophagy and apoptosis. Knockout of endophilin B1 leads to mislocalization of dynamin 2, impaired Golgi fission and inhibition of autophagy. Endophilin B1 also promotes oligomerization of pro-apoptotic protein Bax at mitochondrial outer membranes (MOM), and as such plays a critical role in the regulation MOM permeability and subsequently, apoptosis.
Our previous data show that neuronal-specific isoform of endophilin, endophilin A1, regulates plasma membrane fission during clathrin-mediated endocytosis by controlling assembly of dynamin 1 scaffolds at necks of clathrin-coated pits (ccps). Endophilin A1 and dynamin 1 co-assemble into a scaffold on necks of ccps in vivo and on tubulated liposomes in vitro. Our preliminary cryo-EM 3D reconstruction of the endophilin A1-dynamin 1 macromolecular complex indicates that endophilin A1 regulates plasma membrane fission by controlling dynamin scaffold assembly and GTPase activity. Based on these findings, we propose that endophilins function as membrane templates for members of the dynamin family and Bax to coordinate membrane-remodeling events during crucial cellular pathways that control cell fate. As such, endophilin B1 may play an important tumor suppressor role in the cell. We hypothesize that endophilin B1 macromolecular complex assembly is a universal mechanism that contributes to a wide variety of fundamental cellular processes beyond programmed cell death and tumor suppression and by revealing the mechanisms underlying endophilin B1-mediated membrane remodeling we will shed light on critical cellular processes.
To test our hypothesis, we study the structures and functions of endophilin macromolecular complexes and describe the step-by-step process of complex assembly. To achieve these goals, we use cryo-EM and cell-free assays in combination with functional cell models. We are specifically interested in the molecular mechanisms underlying endophilin B1-dynamin 2-mediated membrane remodeling and autophagosome formation. Are we are currently exploring if endophilin B1 facilitates recruitment of dynamin 2 to Golgi membrane, how endophilin B1 may regulate the assembly and function of dynamin 2 on Golgi membrane, and the mechanisms of endophilin B1-dynamin 2-mediated Golgi scission during autophagosome formation and lysosomal degradation. We are also in the process of determining the role of endophilin B1 in regulation of mitochondrial dynamics and Bax-mediated apoptosis. We are investigating the role of endophilin B1 as a regulator of Bax-mediated apoptosis by unraveling the molecular mechanisms underlying Bax recruitment, activation and assembly at the mitochondrial outer membrane (MOM). We are currently testing the hypothesis that endophilin B1 regulates Bax activation and pore formation at the MOM and that members of the dynamin family and Bax, in turn may regulate the membrane remodeling activity of endophilin B1. We specifically aim to define the regulatory role of endophilin B1 in Bax conformational changes, mitochondrial outer membrane permeabilization and apoptosis, determine if endophilin B1 membrane remodeling activity is auto-inhibited, and how it may be regulated by binding partners.
Anna C. Sundborger, Ph.D.
Assistant Professor and Section Leader
The Hormel Institute
Masonic Cancer Center
University of Minnesota
12:00 pm at Van Andel Institute
Conference Room 3104/3105
For questions, please contact Kim Cousineau at 616.234.5684.