Hypoxia-induced Autophagy is mediated through HIF-induction of BNIP3 and BNIP3L via their BH3-domains.

Description

While HIF is a major actor in the cell survival response to hypoxia, HIF is also associated with cell death. Several studies implicate the HIF-induced putative BH3-only pro-apoptotic genes bnip3 and bnip3L in hypoxia-mediated cell death. We, like others, do not support this assertion. Here we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. Ablation of Beclin1, a major actor of autophagy, enhances cell death under hypoxic conditions. In addition, ablation of BNIP3 and/or BNIP3L triggers cell death and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. First, while siRNA mediated ablation of either BNIP3 or BNIP3L has little effect on autophagy, combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy. Second, ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy. Third, 20-mer BH3-peptides of BNIP3 or BNIP3L are sufficient in initiating autophagy in normoxia. Herein, we propose a model in which the atypical BH3-domains of hypoxia-induced BNIP3/BNIP3L have been 'designed' to induce autophagy by disrupting the Beclin1-Bcl-2 complex without inducing cell death. Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression.

Abstract

International audience

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