CANDIDATE and ENVIRONMENT: I finished my graduate studies on the relationship of glucose metabolism and calcium signaling in yeast in Sept. 1999 (Mentor Dr. David Bedwell, Dept. of Microbiology, UAB). Subsequently, I joined Dr Sztul's group, where my goal has been to develop my interests in protein traffic and degradation. I selected to analyse CFTR biogenesis, since defects in its processing, and subsequent degradation are responsible for Cystic Fibrosis (CF). Dr. Sztul's expertise in ER to Golgi protein transport and a strong CF research team at UAB provide a unique and stimulating environment that is ideal for attaining my goal of becoming an independent scientist studying mechanism of protein turnover. RESEARCH: One single mutation (deltaF508) in CFTR accounts for most of the CF pathology. CFTR functions as a chloride channel on the plasma membrane while (deltaF508 CFTR is retained in the endoplasmic reticulum (ER) and eventually degraded. We hypothesize that an efficient sorting machinery selects CFTR for degradation and underscores the pathogenesis caused by (F508 CFTR. We propose three specific aims to identify novel proteins involved in sorting CFTR for degradation. 1) Identify regulators of CFTR degradation. We have used yeast as a model system to recapitulate CFTR degradation in mammalian cells, and demonstrated that the Sar1p/COPII machinery influences CFTR degradation. We now plan to use a genetic screen and biochemical approaches to identify additional components that regulate CFTR degradation. 2) Regulators identified in Aim 1 will be analyzed for their role in the sorting of CFTR to degradation. 3) Proteins identified to be involved in CFTR degradative sorting in yeast will be examined for their functions in CFTR degradation in mammalian cells. The combined studies with yeast and mammalian cells provide a unique opportunity to identify putative regulators of CFTR degradation. Such study is essential for rational design of therapeutic agents that may prevent CFTR degradation.
| Fu, Lianwu; Sztul, Elizabeth (2009) ER-associated complexes (ERACs) containing aggregated cystic fibrosis transmembrane conductance regulator (CFTR) are degraded by autophagy. Eur J Cell Biol 88:215-26 |
| Fu, Lianwu; Gao, Ya-Sheng; Tousson, Albert et al. (2005) Nuclear aggresomes form by fusion of PML-associated aggregates. Mol Biol Cell 16:4905-17 |
| Fu, Lianwu; Gao, Ya-sheng; Sztul, Elizabeth (2005) Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine protein. Neurobiol Dis 20:656-65 |
