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

Yanyan Zhu, Stefan Massen, Marco Terenzio, Verena Lang, Silu Chen-Lindner, Roland Eils, Ivana Novak, Ivan Dikic, Anne Hamacher-Brady, Nathan Ryan Brady

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1099-1113
Number of pages15
JournalJournal of Biological Chemistry
Volume288
Issue number2
DOIs
StatePublished - Jan 11 2013
Externally publishedYes

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Mitochondrial Degradation
Phosphorylation
Serine
Autophagy
Mitochondria
Modulation
Apoptosis
Cytochromes c
Degradation
Proteins
Flow cytometry
Flow Cytometry
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. / Zhu, Yanyan; Massen, Stefan; Terenzio, Marco; Lang, Verena; Chen-Lindner, Silu; Eils, Roland; Novak, Ivana; Dikic, Ivan; Hamacher-Brady, Anne; Brady, Nathan Ryan.

In: Journal of Biological Chemistry, Vol. 288, No. 2, 11.01.2013, p. 1099-1113.

Research output: Contribution to journalArticle

Zhu, Yanyan ; Massen, Stefan ; Terenzio, Marco ; Lang, Verena ; Chen-Lindner, Silu ; Eils, Roland ; Novak, Ivana ; Dikic, Ivan ; Hamacher-Brady, Anne ; Brady, Nathan Ryan. / Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 2. pp. 1099-1113.
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