Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of studies, mostly performed ex vivo, suggest that lysosomes are involved in apoptosis as a result of a release of their cathepsins into the cytosol. These enzymes could then contribute to the permeabilization of the outer mitochondrial membrane; they could also activate effector caspases. The present study aims at testing whether the membrane of liver lysosomes is disrupted during Fas-mediated cell death of hepatocytes in vivo, a process implicated in several liver pathologies. Apoptosis was induced by injecting mice with aFas (anti-Fas antibody). The state of lysosomes was assessed by determining the proportion of lysosomal enzymes (beta-galactosidase, beta-glucuronidase, cathepsin C and cathepsin B) present in homogenate supernatants, devoid of intact lysosomes, and by analysing the behaviour in differential and isopycnic centrifugation of beta-galactosidase. Apoptosis was monitored by measuring caspase 3 activity (DEVDase) and the release of sulfite cytochrome c reductase, an enzyme located in the mitochondrial intermembrane space. Results show that an injection of 10 microg of aFas causes a rapid and large increase in DEVDase activity and in unsedimentable sulfite cytochrome c reductase. This modifies neither the proportion of unsedimentable lysosomal enzyme in the homogenates nor the behaviour of lysosomes in centrifugation. Experiments performed with a lower dose of aFas (5 microg) indicate that unsedimentable lysosomal hydrolase activity increases in the homogenate after injection but with a marked delay with respect to the increase in DEVDase activity and in unsedimentable sulfite cytochrome c reductase. Comparative experiments ex vivo performed with Jurkat cells show an increase in unsedimentable lysosomal hydrolases, but much later than caspase 3 activation, and a release of dipeptidyl peptidase III and DEVDase into culture medium. It is proposed that the weakening of lysosomes observed after aFas treatment in vivo and ex vivo results from a necrotic process that takes place late after initiation of apoptosis.
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PMID:Lysosomes and Fas-mediated liver cell death. 1712 11

Influenza A virus (IAV) exploits host factors to multiply and cause disease. An in-depth knowledge of this interaction of IAV with the host will aid the development of anti-IAV intervention strategies. Previously, we demonstrated that host cortactin, an actin filament-binding protein promotes IAV infection, but undergoes degradation via a lysosome-associated apoptotic pathway during the late stages of IAV infection. Next, we wanted to further understand the mechanisms and significance of this phenomenon. By using the RNA interference screens and site-directed mutagenesis followed by western blotting, we found that lysosome protease, cathepsin C is involved in cortactin degradation in human cells infected with IAV. Furthermore, executioner apoptotic caspase, caspase-3 not caspase-6 or caspase-7 is involved in cortactin degradation during IAV infection, and caspase-3 cleavage site is located in the first actin-binding repeat of cortactin polypeptide. Finally, when expressed ectopically, the cleavage-resistant cortactin mutants decreased the amount of IAV progeny released from infected cells that was enhanced by the cleavage-sensitive cortactin wild type. These data strengthen the hypothesis proposed earlier that host cortactin plays an inhibitory role during the late stages of IAV infection, and IAV is facilitating its degradation to undermine such function.
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PMID:Caspase-Mediated Cleavage of Human Cortactin during Influenza A Virus Infection Occurs in Its Actin-Binding Domains and Is Associated with Released Virus Titres. 3194 Sep 55