Ubr1 mediates conserved mitophagy
Abstract
Mitophagy is a selective autophagic process that controls mitochondrial homeostasis. Although Parkin has been identified as a mammalian E3 ubiquitin ligase for mitophagy, its homologues do not exist in yeast. Here, we demonstrate that E3 ligase Ubr1 mediates mitophagy in yeast with its evolutionary counterparts UBR1 and UBR2 (UBR1/2) acting independently and in parallel with Parkin in mammalian cells. The new function of Ubr1 ubiquitylating mitochondrial proteins via the non-N-end rule was identified. Structurally and mechanistically, with the assistance of Hsp70, the C-terminus of Ubr1 directly binds β-hairpin on mitochondrial proteins and ubiquitinates the lysine located within the β-hairpin loop, leading to autophagosomal protein LC3 recruitment to mitochondria. A physical complex of Hsp70-Ubr1-VDAC1 is required for Ubr1 translocation to the mitochondria and act there. The conservation of Ubr1 (UBR1/2) mediated mitophagy and the widespread expression of UBR1/2 in neuronal and cancer cells render them a more pivotal target than Parkin, especially since UBR1 overexpression provides stronger neuroprotection than Parkin in dopaminergic (DA) cells. The repurposing of antipsychotic drug clozapine in anti-triple negative breast cancer (TNBC) through UBR2 binding demonstrates that UBR1/2 are druggable targets for mitophagy-associated diseases.
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