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)

Molluscum contagiosum virus proteins MC159 and MC160 and the equine herpesvirus 2 protein E8 share substantial homology to the death effector domain present in the adaptor molecule Fas-associated death domain protein (FADD) and the initiating death protease FADD-like interleukin-1beta-converting enzyme (FLICE) (caspase-8). FADD and FLICE participate in generating the death signal from both tumor necrosis factor receptor-1 (TNFR-1) and the CD-95 receptor. The flow of death signals from TNFR-1 occurs through the adaptor molecule tumor necrosis factor receptor-associated death domain protein (TRADD) to FADD to FLICE, whereas for CD-95 the receptor directly communicates with FADD and then FLICE. MC159 and E8 inhibited both TNFR-1- and CD-95-induced apoptosis as well as killing mediated by overexpression of the downstream adaptors TRADD and FADD. Neither viral molecule, however, inhibited FLICE-induced killing, consistent with an inhibitory action upstream of the active death protease. These data suggest the existence of a novel strategy employed by viruses to attenuate host immune killing mechanisms. Given that bovine herpesvirus 4 protein E1.1 and Kaposi's sarcoma associated-herpesvirus protein K13 also possess significant homology to the viral inhibitory molecules MC159, MC160, and E8, it may be that this class of proteins is used ubiquitously by viruses to evade host defense.
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PMID:A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. 909 88

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein (RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2-/- mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-xL, p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.
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PMID:A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. 1453 86

Infection with human herpes virus 8 (HHV8) has been associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. HHV8 encodes for a viral FLICE-inhibitory protein (vFLIP), designated K13, which resembles the prodomain of caspase-8 in structure and has been shown to protect cells against death receptor-induced apoptosis in vitro and in vivo. In this report, we present evidence that HHV8 vFLIP also possesses the unique ability of transforming Rat-1 and Balb/3T3 fibroblast cells, which is not shared by other vFLIPs. Rat-1 cells expressing HHV8 vFLIP form colonies in soft agar and form tumors in nude mice. The transforming ability of HHV8 vFLIP is associated with the activation of the NF-kappaB pathway and is blocked by molecular and chemical inhibitors of this pathway. Our results suggest that vFLIP K13 has activity beyond its role as an inhibitor of death receptor signaling and may play a causative role in the pathogenesis of HHV8-associated malignancies. Furthermore, inhibitors of the NF-kappaB pathway may have a role in the treatment of malignancies linked to HHV8 infection.
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PMID:The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation. 1456 55