Investigating the novel functions of Rab24 in mitochondrial fission and protein secretion

• Applicants: Professor Christian Behrends, Ph.D.; Professorin Anja Zeigerer, Ph.D.
• Subject Area: Cell Biology ; Biochemistry ; Endocrinology, Diabetology, Metabolism
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 378889372

Membrane trafficking is an essential physiological process responsible for the sorting and distribution of cargoes between different intracellular compartments and the plasma membrane. This highly dynamic and complex process is mediated via transport vesicles. Multiple protein complexes, among them Rab GTPases and their effectors, are responsible for mediating the budding, motility, specificity and fusion of these transport vesicles with the corresponding membranes. Thus, it is not surprising that a dysregulation and missorting in these transport steps are associated with many human diseases, including cancer, neurodegeneration, cardiovascular diseases, immune deficiencies and others.Increasing evidences have begun to support a role for membrane trafficking in metabolic homeostasis. Besides the classical examples of regulated insulin secretion in β-cells and the translocation of the glucose transporter 4 (GLUT4) in fat and muscle cells, our work has established Rab5 and the endosomal system as regulators of liver glucose and lipid metabolism. In addition, diet induced obese mice have been shown to develop profound alterations in the secretory pathway in the liver, leading to a redistribution of Golgi proteins to lipid droplets and a decrease in protein secretion. Recently, we have discovered novel functions of the ER localized Rab24 in mitochondrial function and metabolic control. Rab24 acts as a regulator of mitochondrial fission through its interaction with the fission protein (Fis1), participating in the adaptation of the mitochondrial network to metabolic cues. KD of Rab24 increased mitochondrial connectivity, function, Fgf21 secretion and autophagic flux with immediate impact on hepatic steatosis and glucose metabolism. Interestingly, using an unbiased interactome studies we have identified multiple novel interaction partners of Rab24, in addition to Fis1, which are important in protein secretion in the secretory pathway. Consequently, the present proposal aims at understanding the regulation and physiological significance of the Rab24/Fis1 interaction. In addition, we want to shed light into other Rab24 interactors and its potential function in the egress of proteins from the ER. Finally, we aim to elucidate to what extend Rab24 acts as a molecular switch in response to environmental stimuli between the ER and mitochondria to coordinate or prioritize secretion and/or mitochondrial fission. Thus, the proposed study addresses novel functions of an understudied Rab protein Rab24, and expands our knowledge on mitochondrial fission and network formation as well as protein secretion in relation to the physiological fasting/feeding response.

• DFG Programme: Research Grants