Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis.
We previously cloned Siva-1 by using the cytoplasmic tail of CD27, a member of the tumor necrosis factor receptor family, as the bait in the yeast two-hybrid system. The Siva gene is organized into four exons that code for the predominant full-length Siva-1 transcript, whereas its alternate splice form, Siva-2, lacks exon 2 coding sequence. Various groups have demonstrated a role for Siva-1 in several apoptotic pathways. Interestingly, the proapoptotic properties of Siva-1 are lacking in Siva-2. The fact that Siva-1 is partly localized to mitochondria despite the absence of any mitochondrial targeting signal, it harbors a 20-aa-long putative amphipathic helical structure that is absent in Siva-2, and that its expression is restricted to double-positive (CD3(+), CD4(+), CD8(+)) thymocytes like BCL-X(L), prompted us to test for a potential interaction between Siva-1 and BCL-X(L). Here, we show that Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis. Indeed, the unique amphipathic helical region (SAH) present in Siva-1 is required for its binding to BCL-X(L) and sensitizing cells to UV radiation. Natural complexes of Siva-1/BCL-X(L) are detected in HUT78 and murine thymocyte, suggesting a potential role for Siva-1 in regulating T cell homeostasis.
Xue
Li
L
Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Chu
Fei
F
Cheng
Yuan
Y
Sun
Xiangjie
X
Borthakur
Alip
A
Ramarao
Manjunath
M
Pandey
Pramod
P
Wu
Mei
M
Schlossman
Stuart F
SF
Prasad
Kanteti V S
KV
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; C106549:SIVA1 protein, human; D051020:bcl-X Protein