Our group has two major research interests: investigating the biochemical mechanisms by which the 26S proteasome degrades polyubiquitinated proteins; and identifying modulators that play essential roles in stabilizing the spinal muscular atrophy protein SMN.
The 26S proteasome-mediated protein The 26S proteasome is an approximately 3 Mega Dalton large protein complex that is responsible for degradation of the majority of intracellular proteins in human cells. Usually, protein substrates of the 26S proteasome are modified with a polyubiquitin chain through a cascade of enzymatic reactions requiring a ubiquitin activating enzyme E1, a ubiquitin conjugating enzyme E2 and a ubiquitin ligase E3. There are more than one thousand enzymes that are involved in mediating protein ubiquitination and deubiquitination. Deregulation of the ubiquitin-proteasome system is involved in the pathogenesis and pathophysiology of numerous human diseases including cancer. We are interested in understanding how the 26S proteasome degrades polyubiquitinated proteins and how the activity of the 26S proteasome is regulated in cells by using biochemical and cell biological approaches.
Identifying protein modulators that stabilize SMN at the posttranscriptional level Spinal muscular atrophy (SMA) is the leading genetic disorder for causing infant death, with an incidence of 1/6,000 in living birth. SMA is caused by low levels of survival motor neuron (SMN) protein, although the disease pathogenesis is unknown. Studies using mice have suggested that increase of SMN protein levels can ameliorate the disease symptom and significantly extend the life span of SMA mice. Our goal is to utilize a genome-wide screening to identify modulators that play important roles in mediating SMN protein levels at the posttranscriptional level and to mechanistically understand how these modulators regulate the SMN protein levels and functions. Therapeutically, we expect that some of the identified modulators are potential drug targets of SMA.