Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies

Hyungjin Kim, Mubina Rafiuddin-Shah, Ho Chou Tu, John R. Jeffers, Gerard P. Zambetti, James J.D. Hsieh, Emily H.Y. Cheng

Research output: Contribution to journalArticlepeer-review

693 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1348-1358
Number of pages11
JournalNature Cell Biology
Volume8
Issue number12
DOIs
StatePublished - Dec 2006

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