Microtubule-associated Protein 1 Light Chain 3 (LC3) Interacts with Bnip3 Protein to Selectively Remove Endoplasmic Reticulum and Mitochondria via Autophagy*

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

703 citations recorded by the source corpus.

Background: Bnip3, a protein involved in initiation of cardiovascular disease and cancer, induces autophagy of damaged organelles by a poorly understood mechanism. Results: Bnip3 homodimerization and binding to LC3 induces selective autophagy of mitochondria and ER. Conclusion: Bnip3 plays a direct and selective role in autophagy. Significance: Our studies will advance future studies investigating the role of Bnip3 in human disease. 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 b5. 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.

Subfields: Biochemistry, Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/d1380e685ecbdce059e553e467b5087a2180b355

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Citations in the corpus

Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control (2012, background): “In mammalian cells, mitochondrial NIX/BNIP3L and BNIP3 have been identified as autophagy receptors for the selective clearance of mitochondria in cells.(9,117,118) We have found that BNIP3 promotes mitophagy in cells including cardiac myocytes.”
Recent insights into the function of autophagy in cancer (2016, background): “These mitophagy adaptors interact directlywith processed LC3 and promote an overall reduction in mitochondrial mass as an adaptive response to stresses (Novak et al. 2010; Hanna et al. 2012; Liu et al. 2012; Chourasia et al. 2015a).”
Molecular mechanisms and physiological functions of mitophagy (2021, neutral): “…includes BNIP3 and BNIP3L (also known as NIX) (Boyd et al , 1994; Matsushima et al , 1998; Chen et al , 1999; Vande Velde et al , 2000; Regula et al , 2002; Kubli et al , 2007; Schweers et al , 2007; Sandoval et al , 2008; Hanna et al , 2012), and the other group includes FUNDC1 (Liu et al , 2012).”
Cellular and molecular mechanisms of muscle atrophy (2013, neutral): “2) (Bothe et al., 2000; Hara et al., 2006).”
The mitophagy pathway and its implications in human diseases (2023, background): “In response to stress signals (such as hypoxia), BNIP3 forms a stable homodimer via its C-TM domain and anchors to the OMM.(98) Deletion of the transmembrane domain disrupts dimer formation and results in defective mitophagy, suggesting that homodimerization of BNIP3 is crucial for mitophagy.”
The LIR motif – crucial for selective autophagy (2013, background): “Bnip3 induces the removal of both mitochondria and endoplasmic reticulum (Hanna et al., 2012).”