Abstract

Clearance of extracellular debris and dying cells is essential to preserve multicellular tissue homeostasis, particularly in the liver where low-grade apoptosis and replacement of dead hepatocytes occurs by regeneration. Very recently, a new pathway was described that mediates degradation of extracellular material by phagocytic cells, the LC3 associated phagocytosis (LAP) pathway that uses components of the autophagy pathway to conjugate autophagy protein LC3 to phagosomes, thus facilitating fusion with lysosomes and cargo degradation. Our team led research demonstrating that the dWD domain of ATG16L1 is essential for activation of LAP. We also showed, in genetically-modified mice (which we generated) both with LAP depleted systemically or specifically in myeloid cells, that LAP is key to preservation of brain homeostasis and protection of the lung from influenza. Despite this, the role of LAP in hepatocytes remains unknown. This project will define the role of LAP in hepatocytes for regulation of liver responses to injury and regeneration. We will characterise the LAP machinery in primary hepatocytes, define the stimuli triggering LAP, and determine the functional consequences of its activation in these cells. Next, we will define how LAP in hepatocytes influences the liver response to acute and chronic hepatocellular injury in wild-type and LAP-hepatocyte-deficient mice and how it influences the function of all the different liver cells using high-throughput single cell sequencing technology. Ultimately, we will determine how LAP modulates liver regeneration after challenge via modulation of hepatocyte proliferation. We anticipate providing new fundamental knowledge on how LAP in hepatocytes modulates liver responses to injury. This will inform future research to improve liver responses to injury and prevent/treat disease progression by targeting LAP in a cell-specific manner.