HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP).
The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T-cell leukemia/lymphoma (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance toward CD95-mediated apoptosis. We show that Tax-expressing T-cell lines derived from HTLV-1-infected patients express elevated levels of c-FLIP(L) and c-FLIP(S). The levels of c-FLIP correlated with resistance toward CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance toward CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance toward CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.
Krueger
Andreas
A
Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Fas
Stefanie C
SC
Giaisi
Marco
M
Bleumink
Marc
M
Merling
Anette
A
Stumpf
Christine
C
Baumann
Sven
S
Holtkotte
Denise
D
Bosch
Valerie
V
Krammer
Peter H
PH
Li-Weber
Min
M
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017931:DNA Primers; D017353:Gene Deletion; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D019169:Jurkat Cells; D007700:Kinetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics; D019014:fas Receptor / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017931:DNA Primers; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D019014:fas Receptor