TY - JOUR
T1 - Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies
AU - Kim, Hyungjin
AU - Rafiuddin-Shah, Mubina
AU - Tu, Ho Chou
AU - Jeffers, John R.
AU - Zambetti, Gerard P.
AU - Hsieh, James J.D.
AU - Cheng, Emily H.Y.
N1 - Funding Information:
We would like to thank N. Inohara, E. Johnson and H. Harada for generously providing Hrk, Dp5 and Bim knockdown constructs. E.H-Y.C. is supported by the National Cancer Institute (NCI) Howard Temin Award, Searle Scholars Program and Edward Mallinckrodt, Jr. Foundation. G.P.Z. is supported by a National Institutes of Health (NIH) grant (CA63230).
PY - 2006/12
Y1 - 2006/12
N2 - Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-XL-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-XL -MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-XL to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.
AB - Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-XL-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-XL -MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-XL to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.
UR - https://www.scopus.com/pages/publications/33751513394
U2 - 10.1038/ncb1499
DO - 10.1038/ncb1499
M3 - Article
C2 - 17115033
AN - SCOPUS:33751513394
SN - 1465-7392
VL - 8
SP - 1348
EP - 1358
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 12
ER -