Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lyssaviruses, which are members of the Rhabdoviridae family, induce apoptosis, which plays an important role in the neuropathogenesis of rabies. However, the mechanisms by which these viruses mediate neuronal apoptosis have not been elucidated. Here we demonstrate that the early induction of apoptosis in a model of lyssavirus-infected neuroblastoma cells involves a TRAIL-dependent pathway requiring the activation of caspase-8 but not of caspase-9 or caspase-10. The activation of caspase-8 results in the activation of caspase-3 and caspase-6, as shown by an increase in the cleavage of the specific caspase substrate in lyssavirus-infected cells. However, neither caspase-1 nor caspase-2 activity was detected during the early phase of infection. Lyssavirus-mediated cell death involves an interaction between TRAIL receptors and TRAIL, as demonstrated by experiments using neutralizing antibodies and soluble decoy TRAIL-R1/R2 receptors. We also demonstrated that the decapsidation and replication of lyssavirus are essential for inducing apoptosis, as supported by UV inactivation, cycloheximide treatment, and the use of bafilomycin A1 to inhibit endosomal acidification. Transfection of cells with the matrix protein induced apoptosis using pathways similar to those described in the context of viral infection. Furthermore, our data suggest that the matrix protein of lyssaviruses plays a major role in the early induction of TRAIL-mediated apoptosis by the release of a soluble, active form of TRAIL. In our model, Fas ligand (CD95L) appears to play a limited role in lyssavirus-mediated neuroblastoma cell death. Similarly, tumor necrosis factor alpha does not appear to play an important role.
 ...
PMID:Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. 1516 47

Previously, it has been shown that the laboratory attenuated rabies virus CVS-B2C, but not the wild-type virus SHBRV, induces apoptosis in mice and the induction of apoptosis is mediated by viral glycoprotein. Induction of apoptosis by CVS-B2C limits the spread of the virus in the CNS. In the present study, we characterized the pathways by which CVS-B2C induces apoptosis. BSR cells were infected with CVS-B2C or SHBRV and harvested at different time points for detection of apoptosis by immunofluorescence and flow cytometry. Apoptosis was detected only in cells infected with CVS-B2C, but not SHBRV. Caspase activity and expression of several apoptotic proteins were analyzed by fluorometric assay and Western blotting. Activation of caspase-8 and -3, but not of caspase-9, was observed in CVS-B2C-infected cells. In addition, the level of expression of Apaf-1 did not change. Furthermore, PARP was cleaved confirming activation of downstream caspases. All these data suggest that CVS-B2C infection activates the extrinsic, but not the intrinsic, apoptotic pathway. In addition, AIF, a caspase-independent apoptotic protein was up-regulated and translocated from the cytoplasm to the nucleus post-infection, suggesting that apoptosis induced by CVS-B2C also involves the activation of a caspase-independent pathway.
 ...
PMID:Rabies virus-induced apoptosis involves caspase-dependent and caspase-independent pathways. 1681 22