In:
Journal of Cell Science, The Company of Biologists
Abstract:
Oxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) feeding the porphyrinogenic drug 3, 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and, (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin-IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin-IX or N-methyl-protoporphyrin, or incubating purified lamins with protoporphyrin-IX also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and may serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins.
Type of Medium:
Online Resource
ISSN:
1477-9137
,
0021-9533
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2013
detail.hit.zdb_id:
219171-4
detail.hit.zdb_id:
1483099-1
SSG:
12
