CEBPB, C19MC, and Defective Autophagy Drive Novel Podosomal Belt to Macropinocytosis Transition, Lipid Accumulation,...

Obesity and neurodegeneration are clinically associated diseases with defective autophagy. However, the genetic, biological, and metabolic underpinnings connecting these diseases are not well-understood. Here we identified a Mitochondria^{obesity/neurodegeneration} (M^on) gene-signature that is shared between obesity, and neurodegenerative diseases. We demonstrate that, CEBPB elevates M^on-gene-signature, to form podosomal belts, and enhance ROS production. Inhibiting autophagy collapses podosomal-belts through macropinocytosis to accumulate vacuoles, lipid-droplets, nuclear Notch-1 (nNICD), DEPTOR, and HBV-polymerase mRNAs. Conversely, hemin counteracts these events and suppresses DEPTOR and HBV-polymerase mRNAs by A-to-I-RNA-editing and nonsense-mediated decay. Furthermore, we CRISPR-engineered the antiviral chromosome-19 miRNA cluster (C19MC) to demonstrate that C19MC-miRNAs augment CEBPB, M^on-gene-signature, ROS, and recapitulate CEBPB-driven phenotypes, in response to autophagy inhibition. Hemin, or a γ-Secretase inhibitor counteract these phenotypes in CRISPR-C19MC-engineered cells. Therefore, a CEBPB and C19MC-driven M^on-gene-signature regulates the podosomal belt, lipid droplet, HBV, and DEPTOR mRNA dynamics to genetically link obesity, and neurodegeneration at the cellular level.