Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist.
The prosurvival Bcl-2-family member Bfl-1/A1 is a transcriptional target of nuclear factor-kappaB (NF-kappaB) that is overexpressed in many human tumors and is a means by which NF-kappaB inhibits apoptosis, but its mode of action is controversial. To better understand how Bfl-1 functions, we investigated its interaction with proapoptotic multidomain proteins Bax and Bak, and the BH3-only proteins Bid and tBid. We demonstrate that in living cells Bfl-1 selectively interacts with Bak and tBid, but not with Bax or Bid. Bfl-1/Bak interaction is functional as Bfl-1 suppressed staurosporine (STS)-induced apoptosis in wild-type and Bax-deficient cells, but not in Bak-/- cells. We also show that Bfl-1 blocks tumor necrosis factor-alpha (TNFalpha)-induced activation of Bax indirectly, via association with tBid. C-terminal deletion decreased Bfl-1's interaction with Bak and tBid and reduced its ability to suppress Bak- and tBid-mediated cell death. These data indicate that Bfl-1 utilizes different mechanisms to suppress apoptosis depending on the stimulus. Bfl-1 associates with tBid to prevent activation of proapoptotic Bax and Bak, and it also interacts directly with Bak to antagonize Bak-mediated cell death, similar to Mcl-1. Thus, part of the protective function of NF-kappaB is to induce Mcl-1-like activity by upregulating Bfl-1.
Simmons
M J
MJ
Center for Advanced Biotechnology and Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854-5638, USA.
Fan
G
G
Zong
W-X
WX
Degenhardt
K
K
White
E
E
Gélinas
C
C
D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494772:BAK1 protein, human; C096816:BCL2-related protein A1; D051023:BH3 Interacting Domain Death Agonist Protein; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein