Homozygous (PiZZ) Alpha-1-antitrypsin (alpha1AT) deficiency is the most common genetic cause of liver disease in children. However, the liver injury only occurs in a subpopulation of PiZZ patients and results from the toxic effects of the abnormally folded, mutant alpha1ATZ protein retained with the endoplasmic reticulum (ER) of hepatocytes. We have previously predicted that other genetic traits that would increase the intracellular burden of the Z protein within the ER could predispose this subgroup to liver injury. This hypothesis was tested by obtaining skin fibroblast cell lines from PiZZ patients with liver disease (susceptible hosts) and PiZZ patients without liver disease (protected hosts) and transfecting them to express alpha1ATZ. Skin fibroblasts do not express endogenous alpha1ATZ, although they presumably do exhibit the same characteristics of intracellular protein processing as other host cell types. The result showed that the mutant alpha1ATZ protein was retained within the ER of the cells and then degraded. However, in the susceptible host cells there are relatively inefficiency degradation of the retained alpha1ATZ leading to a net accumulation of the presumable toxic protein. Further analysis has also shown that one pathway for the degradation of retained alpha1ATZ involves the ubiquitin-dependent proteasome degradation pathway present in the cytoplasm. Using an in vitro, cell free translational microsomal translocation system we have identified specific steps in alpha1ATZ degradation leading to the proteasome. Host alterations in one of these steps could cause inefficient degradation. Therefore, we hypothesize that a subgroup of individuals with alpha1AT deficiency are susceptible to liver injury as a result of inherited traits that lead to inefficient degradation of alpha1ATZ protein retained within the ER. We also hypothesize that there are heterogeneous mechanisms that can result in inefficient degradation and that understanding these mechanisms will allow us to predict susceptibility to liver disease in PiZZ patients, develop treatment interventions, and provide new information, in general, about the cellular quality control apparatus that governs secretory proteins.
| Teckman, Jeffrey H (2004) Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study. J Pediatr Gastroenterol Nutr 39:34-7 |
