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Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8512-7. doi: 10.1073/pnas.1406425111. Epub 2014 May 27.

Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak.

Author information

1
Cell Signalling and Cell Death Division andDepartment of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia lindqvist@wehi.edu.au.
2
Cell Signalling and Cell Death Division andDepartment of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
3
Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, AustraliaCancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and.

Abstract

Antiapoptotic B-cell lymphoma 2 (Bcl-2) family members such as Bcl-2, myeloid cell leukemia 1 (Mcl-1), and B-cell lymphoma-X large (Bcl-xL) are proposed to inhibit autophagy by directly binding to the BH3 domain of Beclin 1/Atg6. However, these Bcl-2 family proteins also block the proapoptotic activity of Bcl-2-associated X (Bax) and Bcl-2 homologous antagonist/killer (Bak), and many inducers of autophagy also cause cell death. Therefore, when the mitochondrial-mediated apoptosis pathway is functional, interpretation of such experiments is complicated. To directly test the impact of the endogenous antiapoptotic Bcl-2 family members on autophagy in the absence of apoptosis, we inhibited their activity in cells lacking the essential cell death mediators Bax and Bak. We also used inducible lentiviral vectors to overexpress Bcl-2, Bcl-xL, or Mcl-1 in cells and subjected them to treatments that promote autophagy. In the absence of Bax and Bak, Bcl-2, Bcl-xL, and Mcl-1 had no detectable effect on autophagy or cell death in myeloid or fibroblast cell lines. On the other hand, when Bax and Bak were present, inhibiting the prosurvival Bcl-2 family members stimulated autophagy, but this correlated with increased cell death. In addition, inhibition of autophagy induced by amino acid starvation, etoposide, or interleukin-3 withdrawal did not affect cell death in the absence of Bax and Bak. These results demonstrate that the antiapoptotic Bcl-2 family members do not directly inhibit components of the autophagic pathway but instead affect autophagy indirectly, owing to their inhibition of Bax and Bak.

KEYWORDS:

ABT-737; BH3 mimetic; Bim; LC3; LC3B

PMID:
24912196
PMCID:
PMC4060681
DOI:
10.1073/pnas.1406425111
[Indexed for MEDLINE]
Free PMC Article

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