Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis

• Verfasst von: Zhu, Yanyan [VerfasserIn]
• Verfasst von: Eils, Roland [VerfasserIn]
• Verfasst von: Hamacher-Brady, Anne [VerfasserIn]
• Titel: Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis
• Verf.angabe: Yanyan Zhu, Stefan Massen, Marco Terenzio, Verena Lang, Silu Chen-Lindner, Roland Eils, Ivana Novak, Ivan Dikic, Anne Hamacher-Brady, and Nathan R. Brady
• Jahr: 2013
• Umfang: 15 S.
• Teil: volume:288
• Teil: year:2013
• Teil: number:2
• Teil: pages:1099-1113
• Teil: extent:15
• Fussnoten: Elektronische Reproduktion der Druckausgabe ; Gesehen am 28.07.2021
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : ASBMB Publications, 1905
• Jahr Quelle: 2013
• Band/Heft Quelle: 288(2013), 2, Seite 1099-1113
• ISSN Quelle: 1083-351X
• DOI: doi:10.1074/jbc.M112.399345
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis
• Sach-SW: Autophagy
• Sach-SW: Bcl-2 Family
• Sach-SW: Bcl-xL
• Sach-SW: Bnip3
• Sach-SW: LC3
• Sach-SW: LIR Domain
• Sach-SW: Mitochondria
• Sach-SW: Mitochondrial Apoptosis
• Sach-SW: Mitophagy
• K10plus-PPN: 1764767306

Abstract

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.