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Background & aims

During tumor necrosis factor alpha-mediated hepatocyte cytotoxicity, cathepsin B is released from lysosomes and contributes to apoptosis by indirectly promoting mitochondrial dysfunction. How this lysosomal pathway mediates mitochondrial dysfunction is unclear. Because Bcl-2 family proteins and caspase 2 have been implicated in proximal apoptosis-signaling pathways, we examined the role of these proteins in tumor necrosis factor alpha-induced lysosomal permeabilization and cathepsin B-mediated mitochondrial dysfunction.

Methods

Studies were performed in primary hepatocytes from wild-type cathepsin B knockout, Bid knockout, and caspase 2 knockout mice and in the rat hepatoma cell line McArdle7777 by using tumor necrosis factor alpha/actinomycin D.

Results

Studies in wild-type and Bid knockout hepatocytes showed that tumor necrosis factor alpha-mediated lysosomal permeabilization is Bid dependent. After tumor necrosis factor alpha/actinomycin D treatment, caspase 2 activity increased severalfold in wild-type hepatocytes, whereas minimal activity was observed in hepatocytes from cathepsin B knockout mice or in hepatoma cells treated with a cathepsin B inhibitor. In contrast, Bax was activated independently of cathepsin B. Pharmacological, genetic, or small interfering RNA-mediated inhibition of caspase 2 attenuated tumor necrosis factor alpha-mediated mitochondrial dysfunction, downstream caspase activation, and hepatocyte apoptosis.

Conclusions

These data suggest that tumor necrosis factor alpha triggers Bid-dependent lysosomal permeabilization, followed by release of cathepsin B into the cytosol and activation of caspase 2. Caspase 2 then facilitates efficient mitochondrial cytochrome c release and apoptosis."xsd:string
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http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/author"Yin X.M."xsd:string
http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/author"Gores G.J."xsd:string
http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/author"Bronk S.F."xsd:string
http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/author"Guicciardi M.E."xsd:string
http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/author"Werneburg N.W."xsd:string
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http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
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http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/title"Bid is upstream of lysosome-mediated caspase 2 activation in tumor necrosis factor alpha-induced hepatocyte apoptosis."xsd:string
http://purl.uniprot.org/citations/16012953http://purl.uniprot.org/core/volume"129"xsd:string
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