title: PINK1 is degraded through the N-end rule pathway.
abstract: PINK1, a mitochondrial serine/threonine kinase, is the product of a gene mutated in an autosomal recessive form of Parkinson disease. PINK1 is constitutively degraded by an unknown mechanism and stabilized selectively on damaged mitochondria where it can recruit the E3 ligase PARK2/PARKIN to induce mitophagy. Here, we show that, under steady-state conditions, endogenous PINK1 is constitutively and rapidly degraded by E3 ubiquitin ligases UBR1, UBR2 and UBR4 through the N-end rule pathway. Following precursor import into mitochondria, PINK1 is cleaved in the transmembrane segment by a mitochondrial intramembrane protease PARL generating an N-terminal destabilizing amino acid and then retrotranslocates from mitochondria to the cytosol for N-end recognition and proteasomal degradation. Thus, sequential actions of mitochondrial import, PARL-processing, retrotranslocation and recognition by N-end rule E3 enzymes for the ubiquitin proteosomal degradation defines the rapid PINK1 turnover. PINK1 steady-state elimination by the N-end rule identifies a novel organelle to cytoplasm turnover pathway that yields a mechanism to flag damaged mitochondria for autophagic elimination.
authors.affiliation: Biochemistry Section; Surgical Neurology Branch; National Institute of Neurological Disorders and Stroke; National Institutes of Health; Bethesda, MD USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamano
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D059748:Proteolysis; D000071456:Sequestosome-1 Protein; D000099202:PTEN-Induced Putative Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D011494:Protein Kinases; D000071456:Sequestosome-1 Protein; D000099202:PTEN-Induced Putative Kinase; C099718:SQSTM1 protein, human; C485223:PARL protein, human
keywords: PARKIN; PARL; mitochondrial import; mitophagy; ubiquitin