Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
Apoptosis and autophagy are both tightly regulated biological processes that play a central role in tissue homeostasis, development, and disease. The anti-apoptotic protein, Bcl-2, interacts with the evolutionarily conserved autophagy protein, Beclin 1. However, little is known about the functional significance of this interaction. Here, we show that wild-type Bcl-2 antiapoptotic proteins, but not Beclin 1 binding defective mutants of Bcl-2, inhibit Beclin 1-dependent autophagy in yeast and mammalian cells and that cardiac Bcl-2 transgenic expression inhibits autophagy in mouse heart muscle. Furthermore, Beclin 1 mutants that cannot bind to Bcl-2 induce more autophagy than wild-type Beclin 1 and, unlike wild-type Beclin 1, promote cell death. Thus, Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1. This antiautophagy function of Bcl-2 may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.
Pattingre
Sophie
S
Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA.
Tassa
Amina
A
Qu
Xueping
X
Garuti
Rita
R
Liang
Xiao Huan
XH
Mizushima
Noboru
N
Packer
Milton
M
Schneider
Michael D
MD
Levine
Beth
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects* / Q000378:metabolism; D013217:Starvation / Q000517:prevention & control
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D029701:Saccharomyces cerevisiae Proteins; C491997:BECN1 protein, human; C505334:Beclin 1 protein, S cerevisiae; C115010:Becn1 protein, mouse