Degradation of Mcl-1 by granzyme B: Implications for Bim-mediated mitochondrial apoptotic events

Jie Han, Leslie A. Goldstein, Brian R. Gastman, Christopher J. Froelich, Xiao Ming Yin, Hannah Rabinowich

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83 Scopus citations

Abstract

Recent studies have suggested that in the absence of Bid, granzyme B (GrB) can utilize an unknown alternative pathway to mediate mitochondrial apoptotic events. The current study has elucidated just such a pathway for GrB-mediated mitochondrial apoptotic alterations. Two Bcl-2 family members have been identified as interactive players in this newly discovered mitochondrial response to GrB: the pro-survival protein Mcl-1L and the pro-apoptotic protein, Bim. Expression of Mcl-1L, which localizes mainly to the outer mitochondrial membrane, decreases significantly in cells subjected to CTL-free cytotoxicity mediated by a combination of GrB and replication-deficient adenovirus. The data suggest that Mcl-1L is a substrate for GrB and for caspase-3, but the two enzymes appear to target different cleavage sites. The cleavage pattern of endogenous Mcl-1L resembles that of in vitro translated Mcl-1L subjected to similar proteolytic activity. Co-immunoprecipitation experiments performed with endogenous as well as with in vitro translated proteins suggest that Mcl-1L is a high affinity binding partner of the three isoforms of Bim (extra-long, long, and short). Bim, a BH3-only protein, is capable of mediating the release of mitochondrial cytochrome c, and this activity is inhibited by the presence of exogenous Mcl-1L. The findings presented herein imply that Mcl-1L degradation by either GrB or caspase-3 interferes with Bim sequestration by Mcl-1L.

Original languageEnglish (US)
Pages (from-to)22020-22029
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number21
DOIs
StatePublished - May 21 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Han, J., Goldstein, L. A., Gastman, B. R., Froelich, C. J., Yin, X. M., & Rabinowich, H. (2004). Degradation of Mcl-1 by granzyme B: Implications for Bim-mediated mitochondrial apoptotic events. Journal of Biological Chemistry, 279(21), 22020-22029. https://doi.org/10.1074/jbc.M313234200