Abstract
Bcl-2-interacting cell death suppressor (BIS), also called as BAG3, regulates numerous physiological processes, such as apoptosis, protein quality control, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality following cardiac and skeletal muscle dysfunction. The first attempt to generate organ-specific knockout mice resulted in constitutive or inducible heart-specific Bis-knockout mice, which exhibited cardiac dilation and underwent premature death. Here, we generated hepatocyte-specific Bis-knockout (Bis-HKO) mice and found no abnormalities in metabolic function and survival. However, depletion of HSPB8 and accumulation of p62 indicated impaired autophagy in Bis-HKO livers. Interestingly, the number of peroxisomes wrapped by phagophore membranes increased as evidenced by transmission electron microscopy analysis, indicating defects in the progression of pexophagy. In addition, increased dihydroethidine intensities and histone H3 K9me3-positive nuclei indicated increased oxidative stress and senescence induction in Bis-HKO livers. Mechanistically, p27 was upregulated in Bis-HKO livers. In SNU368 hepatocellular carcinoma cells, BIS depletion led to p27 upregulation, and increase in histone H3 K9me3 levels and senescence-associated β-galactosidase staining; therefore, reproducing the in vivo senescence phenotype. Despite the observation of no metabolic abnormalities, BIS depletion led to defective autophagy, increased oxidative stress, and senescence in Bis-HKO livers. Collectively, our results suggest a role for BIS in maintaining liver regeneration potential under pathological conditions.