Cited by 762Autophagy in Disease and TherapyCell death mechanisms and regulationUbiquitin and proteasome pathways

Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy

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Hanna, Rita A., Quinsay, Melissa N., Orogo, Amabel M., Giang, Kayla, Rikka, Shivaji, Gustafsson, Åsa B.·2012·Journal of Biological Chemistry

Abstract

Autophagy plays an important role in cellular quality control and is responsible for removing protein aggregates and dysfunctional organelles. Bnip3 is an atypical BH3-only protein that is known to cause mitochondrial dysfunction and cell death. Interestingly, Bnip3 can also protect against cell death by inducing mitochondrial autophagy. The mechanism for this process, however, remains poorly understood. Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. Several Bnip3 mutants that do not interfere with its mitochondrial localization but disrupt homodimerization failed to induce autophagy in cells. In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). To investigate the effects of Bnip3 at mitochondria or the ER on autophagy, Bnip3 was targeted specifically to each organelle by substituting the Bnip3 transmembrane domain with that of Acta or cytochrome b(5). We found that Bnip3 enhanced autophagy in cells from both sites. We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. Our data indicate that Bnip3 regulates the apoptotic balance as an autophagy receptor that induces removal of both mitochondria and ER.

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Crossref · 10.1074/jbc.m111.322933

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Authors
Hanna, R. A., Quinsay, M. N., Orogo, A. M., Giang, K., Rikka, S., & Gustafsson, Å. B.
Affiliations
University of California San Diego (US)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2012-06
Volume
287
Issue
23
Pages
19094-19104
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2122556106
Cited by
762
References
46
Citations by year
2026: 54 · 2025: 54 · 2024: 60 · 2023: 60 · 2022: 77 · 2021: 79 · 2020: 71 · 2019: 45 · 2018: 48 · 2017: 42 · 2016: 44 · 2015: 49 · 2014: 40 · 2013: 30 · 2012: 9
FWCI
30.54
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL101217, R01HL087023)
  • National Institute of General Medical Sciences (T32GM007752)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
BNIP3, LC3, autophagy, mitophagy, endoplasmic reticulum, mitochondria, BH3-only proteins, protein homodimerization, autophagy receptors, autophagosomes, transmembrane domain
MeSH terms
Autophagy, Endoplasmic Reticulum, HeLa Cells, Humans, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Mutation, Proto-Oncogene Proteins, Apoptosis, Protein Structure, Tertiary

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