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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Granzymes
Degradation
Caspase 3
Apoptosis Regulatory Proteins
Proteins
Mitochondrial Membranes
Cytotoxicity
Cytochromes c
Immunoprecipitation
Adenoviridae
Protein Isoforms
Membranes
Substrates
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Degradation of Mcl-1 by granzyme B : Implications for Bim-mediated mitochondrial apoptotic events. / Han, Jie; Goldstein, Leslie A.; Gastman, Brian R.; Froelich, Christopher J.; Yin, Xiao-Ming; Rabinowich, Hannah.

In: Journal of Biological Chemistry, Vol. 279, No. 21, 21.05.2004, p. 22020-22029.

Research output: Contribution to journalArticle

Han, Jie ; Goldstein, Leslie A. ; Gastman, Brian R. ; Froelich, Christopher J. ; Yin, Xiao-Ming ; Rabinowich, Hannah. / Degradation of Mcl-1 by granzyme B : Implications for Bim-mediated mitochondrial apoptotic events. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 21. pp. 22020-22029.
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