BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK

Abstract

BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) is an atypical BH3-only protein that is induced by hypoxia-inducible factor 1 (HIF1) under hypoxia. BNIP3 is primarily regulated at the transcriptional level. However, little is known about the underlying mechanism of BNIP3 degradation. In this study, we found that BNIP3 was downregulated when hypoxia was accompanied by amino acid starvation. The BNIP3 downregulation did not occur at the transcription level and was independent of HIF1A. BNIP3 was primarily degraded by the proteasome, but BNIP3 was subjected to both proteasomal and autophagic degradation in response to starvation. The autophagic degradation of BNIP3 was dependent on ATG7 and MAP1LC3. We determined that autophagic degradation of BNIP3 was specifically regulated by ULK1 via the MTOR-AMPK pathway. Moreover, we confirmed that BNIP3 could play a protective role in tumor cells under hypoxia, and the treatment with Torin1, an MTOR inhibitor, decreased the BNIP3 level and enhanced the death of hypoxic tumor cells.

Keywords: :

• hypoxia
• autophagy
• BNIP3
• MTOR
• AMPK
• BECN1
• ULK1
• Torin1

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We sincerely thank Dr. D. Sabatini (Massachusetts Institute of Technology, MA USA) and Dr. N. Gray (Harvard Medical School, MA USA) for generously providing Torin1 and Dr. J. Jung (University of Southern California, CA USA) for providing the pEGFP-MAP1LC3B vector. We also thank Mr. Jae Hyun Park (IPS-TECH) for technical support on the hypoxia experiment. This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korea government (MEST): the National Honor Scientist Support Program (No. 20100020417) and by the WCU program, NRF, MEST, Korea (R31-10105).

Supplemental Materials

Supplemental materials may be found here: www.landesbioscience.com/journals/autophagy/article/23072