engleski

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- 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.

Apoptosis; Autophagy; Bcl-2 Family; Mitochondria; Mitochondrial Apoptosis; Bcl-xL; Bnip3; LC3; LIR Domain; Mitophagy

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