Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD).
Ligation of TCRs on stimulated T cells leads to activation-induced cell death (AICD) resulting in the downregulation of immune responses, a process essential for T-cell homeostasis. In this study, using transformed T-cell lines such as Jurkat and Do11.10 as cellular models of TCR-mediated AICD, we have demonstrated that the proapoptotic protein Siva-1 is required for TCR-induced apoptosis. Knockdown of Siva-1 rendered T cells specifically resistant to anti-CD3 but not Fas-induced apoptosis. Further, we observed that in Siva-1 knockout Jurkat cells, TCR-mediated activation of the canonical and non-canonical limbs of the NF-kappaB pathway are significantly enhanced as reflected by elevated nuclear levels of p65 and RelB, respectively. In addition, loss of endogenous Siva-1 also resulted in the enhanced expression of NF-kappaB- responsive anti-apoptotic genes such as Bcl-xL and c-FLIP. Interestingly, the c-FLIP(short) was detected only in TCR-ligated Siva-1 knockdown Jurkat cells. These results demonstrate a significant role for endogenous Siva-1, through its inhibitory effect on NF-kappaB activity, in TCR-mediated AICD with implications in peripheral tolerance, T-cell homeostasis and cancer.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
R
R
Gudi
J
J
Barkinge
S
S
Hawkins
F
F
Chu
S
S
Manicassamy
Z
Z
Sun
J S
JS
Duke-Cohan
K V S
KV
Prasad
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016923:Cell Death; D002461:Cell Line, Transformed; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D051020:bcl-X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; C106549:SIVA1 protein, human; D051020:bcl-X Protein