Autophagy is the crucial waste cleaning system for the cell. Removal of damage organelles, protein aggregates and invading pathogens relies on autophagy ("self-eating" in Greek). Autophagy is also important for organelle biogenesis and stress response. Dysfunction of autophagy has been implicated in a broad spectrum of human diseases, including cancers, neurodegenerative diseases, infectious diseases and metabolic diseases. During autophagy, a double membrane vesicle termed autophagosome is formed with engulfed cellular cargoes and then fused with lysosomes for degradation. We are specifically interested in dissecting the biochemical mechanisms in this process including lipid modification, membrane deformation, membrane curvature sensing, cargo recruitment, and membrane tethering/fusion. Understanding the key regulatory steps in this pathway will allow us to develop new therapeutic tools for human diseases.
II: Cell death
In an effort to elucidate the signaling pathway for DNA damage induced apoptosis; we identified a HECT domain ubiquitin ligase, Mule, as a key regulator of apoptosis by controlling the polyubiquitination and degradation of anti-apoptotic BCL-2 family protein Mcl-1. Later on, Mule null cells are also found to be resistant to HDAC (histone deacetylase) inhibitors, and we identified HDAC2 as a substrate of Mule and showed that this regulation determines the cellular response to HDACis. Both DNA damaging agents and HDACis are broadly used as first-line anti-cancer drugs. We are continuing to understand the biological functions of Mule in apoptosis and other forms of cell death induced by cancer therapeutic agents.