Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis
BH3-only proteins integrate apoptosis and autophagy pathways, yet regulation and functional consequences of pathway cross-talk are not fully resolved. The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-intera...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2013
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| In: |
The journal of biological chemistry
Year: 2013, Volume: 288, Issue: 2, Pages: 1099-1113 |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M112.399345 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1074/jbc.M112.399345 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0021925820466554 
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| Author Notes: | Yanyan Zhu, Stefan Massen, Marco Terenzio, Verena Lang, Silu Chen-Lindner, Roland Eils, Ivana Novak, Ivan Dikic, Anne Hamacher-Brady, and Nathan R. Brady |
| Summary: | BH3-only proteins integrate apoptosis and autophagy pathways, yet regulation and functional consequences of pathway cross-talk are not fully resolved. The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. Here we report that phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16. Using quantitative multispectral image-based flow cytometry, we demonstrate that enhancing Bnip3-Atg8 interactions via phosphorylation-mimicked LIR mutations increased mitochondrial sequestration, lysosomal delivery, and degradation. Importantly, mitochondria were targeted by mitophagy prior to cytochrome c release, resulting in reduced cellular cytochrome c release capacity. Intriguingly, pro-survival Bcl-xL positively regulated Bnip3 binding to LC3B, sequestration, and mitochondrial autophagy, further supporting an anti-apoptotic role for Bnip3-induced mitophagy. The ensemble of these results demonstrates that the phosphorylation state of the Bnip3 LIR signals either the induction of apoptosis or pro-survival mitophagy. Background: Bnip3 is both a pro-apoptotic BH3-only protein and a mitochondrial autophagy receptor. Results: Serine phosphorylation of the Bnip3 LC3-interacting region (LIR) increased binding to Atg8 members and consequently mitophagy, in a manner positively regulated by Bcl-xL. Conclusion: The Bnip3 LIR activity state determines either pro-survival mitophagy or mitochondrial apoptosis. Significance: Bnip3-induced mitophagy is serine kinase-regulated and thus a targetable pathway. |
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| Item Description: | Elektronische Reproduktion der Druckausgabe Gesehen am 28.07.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M112.399345 |