Mallory bodies formed in proteasome-depleted hepatocytes: An immunohistochemical study

Mallory bodies (MBs) are aggregates of proteins, principally cytokeratin proteins found in liver cells. They are also found in a few other cell types such as type II pneumocytes and trophoblasts. Studies on the liver thus far indicate that MBs are derived from hyperphosphorylated, heavily ubiquitinated proteins which have undergone conformational change. The aggregated protein may accumulate because of the failure of the proteasome to remove the altered proteins from the cytoplasm of liver cells. To investigate this possibility, the proteasomes were assessed immunohistochemically in individual liver cells of mice fed a drug which induced MB formation. To accelerate and enhance MB formation, cytochrome P450 2EI knockout mice were used. Proteasomes in individual cells were visualized by immunofluorescence using an antibody to a subunit of the proteasome (P25). The results showed that the groups of liver cells that had formed MBs were often partially depleted of proteasomes. These findings support the possibility that MBs formed as a result of the loss of the proteasome to remove misfolded cytokeratin proteins. Thus MBs may share their pathogenesis with other types of cellular inclusions seen where proteins aggregate in the cytoplasm due to mutation, misfolding, or loss of proteasomes.