Molecular misreading of the ubiquitin B gene and hepatic mallory body formation.
OBJECTIVE
Molecular misreading of the ubiquitin B gene has been documented in the cerebral cortex of patients with Alzheimer's disease and Down syndrome. This novel process consists of the unfaithful conversion of genomic information into aberrant transcripts and its subsequent translation into +1 proteins.


METHODS
Because Mallory bodies (MBs) also contain ubiquitinated proteins, we stained 11 autopsied and 6 biopsied MB-containing livers from patients with steatohepatitis with an antibody to ubiquitin(+1) to look for the presence of mutant (ubiquitin(+1)) protein. Antibodies to wild-type ubiquitin were used to document the presence of MBs in all cases.


RESULTS
Ubiquitin(+1) immunoreactivity was detected in all MB-containing livers with steatohepatitis; no ubiquitin(+1) immunoreactivity was found in 13 MB-free liver controls. A subpopulation (about one third of the MBs) of the MB-containing hepatocytes in autopsied livers showed ubiquitin(+1) immunoreactivity (i.e., ubiquitin and ubiquitin(+1) colocalized in MBs). MB-containing liver biopsy specimens showed colocalization of ubiquitin and ubiquitin(+1) in every MB. Western blot analysis showed an ubiquitin(+1) band of 11 kilodaltons. Molecular misreading of the ubiquitin B gene (DeltaGU) was shown in one of the livers, which contained numerous MBs using an expression cloning strategy.


CONCLUSIONS
The results showed that molecular misreading of the ubiquitin B gene occurred in hepatocytes in virtually all of the MB-containing livers tested. Ubiquitin(+1) protein was only found within the MBs and therefore may act by interfering with the degradation of the MBs because ubiquitin(+1) may inhibit proteolytic function of the proteasome.
McPhaul
Laron W
LW
Department of Pathology, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California 90509, USA.
Wang
Jun
J
Hol
Elly M
EM
Sonnemans
Marc A F
MA
Riley
Nora
N
Nguyen
Victoria
V
Yuan
Qi Xiao
QX
Lue
Yan-He
YH
Van Leeuwen
Fred W
FW
French
Samuel W
SW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002102:Cadaver; D002648:Child; D005234:Fatty Liver / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007158:Immunologic Techniques; D002479:Inclusion Bodies / Q000502:physiology*; D007223:Infant; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D012016:Reference Values; D014158:Transcription, Genetic / Q000502:physiology*; D025801:Ubiquitin / Q000235:genetics*
D025801:Ubiquitin