# CEBPB, C19MC, and Defective Autophagy Drive Novel Podosomal Belt to Macropinocytosis Transition, Lipid Accumulation, and HBV A-to-I RNA-editing

## TL;DR

This study reveals how defective autophagy and specific genes like CEBPB and C19MC connect obesity and neurodegeneration through cellular changes like lipid accumulation and RNA editing.

## Contribution

The discovery of a shared Mon-gene-signature and its regulation by CEBPB and C19MC linking obesity and neurodegeneration is novel.

## Key findings

- CEBPB elevates a Mon-gene-signature, forming podosomal belts and increasing ROS production.
- Inhibiting autophagy leads to lipid accumulation and HBV RNA editing via macropinocytosis.
- CRISPR-engineered C19MC miRNAs enhance CEBPB-driven phenotypes, which are counteracted by hemin or γ-Secretase inhibitors.

## Abstract

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 Mitochondriaobesity/neurodegeneration (Mon) gene-signature that is shared between obesity, and neurodegenerative diseases. We demonstrate that, CEBPB elevates Mon-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, Mon-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 Mon-gene-signature regulates the podosomal belt, lipid droplet, HBV, and DEPTOR mRNA dynamics to genetically link obesity, and neurodegeneration at the cellular level.