RUBCNL/Pacer and RUBCN/Rubicon in regulation of autolysosome formation and lipid metabolism

Abstract

Recently, we identified a vertebrate-specific macroautophagy/autophagy regulator, RUBCNL/Pacer, which promotes autolysosome formation by engaging the class III phosphatidylinositol 3-kinase (PtdIns3K) and HOPS complexes. Hepatocyte-specific rubcnl knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. We further showed that under nutrient-rich conditions RUBCNL is inactivated by MTORC1-mediated phosphorylation. When nutrients are insufficient, RUBCNL is dephosphorylated, which facilitates its acetylation by the activated GSK3-KAT5/TIP60 pathway. RUBCNL acetylation significantly enhances HOPS complex recruitment, which eventually results in more efficient autophagosome maturation and lipid metabolism both in vitro and in vivo. Therefore, our work not only demonstrates that RUBCNL is essential for hepatic autophagy and liver homeostasis, but also reveals a signal integration mechanism involved in late stages of autophagy and lipid metabolism. Interestingly, these in vitro and in vivo functional data on RUBCNL are partially the opposite of the results from RUBCN/Rubicon studies that were either obtained by us or others. This implies a dual molecular switch model that is controlled by RUBCNL and RUBCN in modulation of autophagosome maturation and lipid metabolism.