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Mallory bodies formed in proteasome-depleted hepatocytes: an immunohistochemical study
F Bardag-Gorce1, B A French, Y H Lue
1Department of Pathology and Medicine, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, California 90509, USA.
Abstract:
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.
Insights
Mallory bodies (MBs), protein aggregates in liver cells, may form due to proteasome dysfunction. This study found liver cells with MBs were often depleted of proteasomes, suggesting impaired protein clearance.
Area of Science:
- Hepatology
- Cell Biology
- Protein Biochemistry
Background:
- Mallory bodies (MBs) are cytoplasmic protein aggregates, primarily cytokeratins, found in hepatocytes.
- MBs are thought to arise from hyperphosphorylated, ubiquitinated proteins with altered conformations.
- The accumulation of these proteins may indicate a failure in cellular protein degradation pathways, such as the proteasome.
Purpose of the Study:
- To investigate the role of proteasome function in the formation of Mallory bodies.
- To determine if proteasome depletion is associated with MB formation in liver cells.
Main Methods:
- Utilized a drug-induced mouse model to promote MB formation.
- Employed cytochrome P450 2E1 knockout mice to enhance MB formation.
- Assessed proteasome levels in individual liver cells using immunohistochemistry and immunofluorescence with an antibody to a proteasome subunit (P25).
Main Results:
- Liver cells containing Mallory bodies frequently showed partial depletion of proteasomes.
- These findings suggest a correlation between reduced proteasome presence and MB accumulation.
Conclusions:
- Mallory body formation may result from the proteasome's inability to clear misfolded cytokeratin proteins.
- MBs might share a common pathogenesis with other cytoplasmic protein aggregation disorders linked to proteasome dysfunction or protein misfolding.