HIV-1 Tat protein concomitantly down-regulates apical caspase-10 and up-regulates c-FLIP in lymphoid T cells: a potential molecular mechanism to escape TRAIL cytotoxicity.
In this study, we showed the existence of a positive correlation between the amount of human immunodeficiency virus-type 1 (HIV-1) RNA in HIV-1 seropositive subjects and the plasma levels of TRAIL. Since it has been previously demonstrated that HIV-1 Tat protein up-regulates the expression of TRAIL in monocytic cells whereas tat-expressing lymphoid cells are more resistant to TRAIL cytotoxicity, we next investigated the effect of Tat on the expression/activity of both apical caspase-8 and -10, which play a key role in mediating the initial phases of apoptosis by TRAIL, and c-FLIP. Jurkat lymphoblastoid human T cell lines stably transfected with a plasmid expressing wild-type (HIV-1) tat gene showed normal levels of caspase-8 but significantly decreased levels of caspase-10 at both mRNA and protein levels with respect to Jurkat transfected with the control plasmid or with a mutated (cys22) non-functional tat cDNA. A significant decrease of caspase-10 expression/activity was also observed in transient transfection experiments with plasmid carrying tat cDNA. Moreover, c-FLIP(L) and c-FLIP(S) isoforms were up-regulated in tat-expressing cells at both mRNA and protein level in comparison with control cells. Taken together, these results provide a molecular basis to explain the resistance of tat-expressing Jurkat cells to apoptosis induced by TRAIL and, possibly, to other death-inducing ligands.
Gibellini
Davide
D
Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy. davide.gibellini@unibo.it
Re
Maria Carla
MC
Ponti
Cristina
C
Vitone
Francesca
F
Bon
Isabella
I
Fabbri
Greta
G
Grazia Di Iasio
Maria
M
Zauli
Giorgio
G
D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015658:HIV Infections / Q000097:blood* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism*; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000097:blood* / Q000633:toxicity; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D015854:Up-Regulation / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D018076:DNA, Complementary; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012367:RNA, Viral; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human