Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 29B, Rm 4NN16, 8800 Rockville Pike, Bethesda, MD, 20892, USA.
c-FLIPL, an inhibitor of caspase 8, is known to inhibit the Fas/caspase 8 apoptotic pathway; however, its involvement of Bax/mitochondrial apoptosis is not well understood. Using human cells, Jurkat cell line, induced with HIV-1 gp120, we studied the effects of c-FLIPL on Bax/mitochondrial apoptosis. We found that the induction of apoptosis by HIV-1 envelope protein, gp120, involved the activation of both Bax-dependent and death receptor-mediated pathways, and HIV-1 infection deceased c-FLIPL expression. Interestingly, c-FLIPL expression downregulated protein kinase C (PKC) expression at the transcript level involving activated protein-2 (AP-2). c-FLIPL expression reduced AP-2 protein levels required to promote PKC protein expression and PKC-associated inactive form of Bax, and inhibited Bax activation, suggesting that c-FLIPL inhibits Bax activation via modulating PKC expression at the transcriptional level involving AP-2 during gp120 treatment. Collectively, these findings further corroborate the concept that gp120 plays an important role, via involvement of molecules such as c-FLIPL, in apoptotic cell death due to HIV-1 infection.
"Caspase-8 is a critical component of DISC where caspase-8 cleavage from its trimer to become the active form of caspase-8 necessary to activate the effector caspases, such as caspase-3, in the downstream of Fas signaling . 1 MOI of virus H1N1pdm- infected A549 cells displayed more caspase-8 cleavage from day 2 (Fig. 3A) which suggests that H1N1pdm infection is able to induce apoptosis in A549 cells through Fas signaling. FLIP, for example, is an inhibitor of caspase-8, and increased recruitment of FLIP into DISC results in blockage of caspase-8 activity  , which inhibits Fas-mediated apoptotic signaling and virus replication (Fig. 2B). To test the effect of caspase-8 inhibition on H1N1pdm production, A549 cells were infected with 1 MOI of virus for 2 h, and then incubated in Fig. 2. Virus infection modulated molecules of components in DISC formation and expression of them impacts viral replication. "
[Show abstract][Hide abstract] ABSTRACT: It is not well-known whether apoptosis signaling affects influenza virus infection and reproduction in human lung epithelial cells. Using A549 cell line, we studied the relationship of some apoptosis-associated molecules with novel pandemic influenza A (H1N1) virus, A/California/04/2009. Infected cells displayed upregulated Fas ligand, activated FADD and caspase-8, and downregulated FLIP in the extrinsic apoptotic pathway. p53 expression increased and Bcl-XL expression decreased in the intrinsic pathway. Expression of pre-apoptotic molecules (FasL, FADD, and p53) increased virus replication, while inhibition of activity of FADD, caspase-8 and caspase-3, and expression of anti-apoptotic proteins (FLIP and Bcl-XL) decreased virus replication. p38, ERK and JNK from MAPK pathways were activated in infected cells, and inhibition with their inhibitors diminished virus replication. In the p38 superfamily, p38α expression increased viral RNA production, while expression of p38β and p38γ decreased. These data indicated that influenza virus induces apoptotic signaling pathways, which benefit virus replication.
Microbes and Infection 11/2013; 16(3). DOI:10.1016/j.micinf.2013.11.003 · 2.86 Impact Factor
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