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FAT10 knock out mice livers fail to develop Mallory-Denk bodies in the DDC mouse model
S W French1, B A French, J Oliva
1Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA 90509, USA. French7@ucla.edu
Abstract:
Mallory-Denk bodies (MDBs) are aggresomes composed of undigested ubiqutinated short lived proteins which have accumulated because of a decrease in the rate of their degradation by the 26s proteasome. The decrease in the activity of the proteasome is due to a shift in the activity of the 26s proteasome to the immunoproteasome triggered by an increase in expression of the catalytic subunits of the immunoproteasome which replaces the catalytic subunits of the 26s proteasome. This switch in the type of proteasome in liver cells is triggered by the binding of IFNγ to the IFNγ sequence response element (ISRE) located on the FAT10 promoter. To determine if either FAT10 or IFNγ are essential for the formation of MDBs we fed both IFNγ and FAT10 knock out (KO) mice DDC added to the control diet for 10weeks in order to induce MDBs. Mice fed the control diet and Wild type mice fed the DDC or control diet were compared. MDBs were located by immunofluorescent double stains using antibodies to ubiquitin to stain MDBs and FAT10 to localize the increased expression of FAT10 in MDB forming hepatocytes. We found that MDB formation occurred in the IFNγ KO mice but not in the FAT10 KO mice. Western blots showed an increase in the ubiquitin smears and decreases β 5 (chymotrypsin-like 26S proteasome subunit) in the Wild type mice fed DDC but not in the FAT10 KO mice fed DDC. To conclude, we have demonstrated that FAT10 is essential to the induction of MDB formation in the DDC fed mice.
Insights
FAT10 is essential for Mallory-Denk body formation in mice fed DDC. Interferon-gamma knockout mice still formed MDBs, but FAT10 knockout mice did not, indicating FAT10
Area of Science:
- Hepatology
- Cellular Biology
- Molecular Mechanisms
Background:
- Mallory-Denk bodies (MDBs) are protein aggregates in hepatocytes, linked to liver injury.
- MDB formation results from impaired protein degradation by the 26S proteasome.
- A shift to the immunoproteasome, triggered by Interferon-gamma (IFNγ), reduces 26S proteasome activity.
Purpose of the Study:
- To investigate the roles of FAT10 and IFNγ in MDB formation.
- To determine if FAT10 or IFNγ are essential for MDB induction in a DDC-fed mouse model.
Main Methods:
- Utilized IFNγ and FAT10 knockout (KO) mice fed DDC diet for 10 weeks to induce MDBs.
- Employed immunofluorescent staining with ubiquitin and FAT10 antibodies to detect MDBs.
- Analyzed protein levels via Western blot to assess proteasome subunit activity.
Main Results:
- MDB formation was observed in IFNγ KO mice but absent in FAT10 KO mice.
- Western blots confirmed increased ubiquitin smears and decreased β5 subunit in DDC-fed wild-type mice, but not in FAT10 KO mice.
- These findings highlight a critical role for FAT10 in MDB pathogenesis.
Conclusions:
- FAT10 is essential for the induction of Mallory-Denk bodies in DDC-fed mice.
- IFNγ is not essential for MDB formation under these experimental conditions.
- The study elucidates a key molecular pathway in MDB development.
