title: The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking.
abstract: Intramembrane proteolysis is a conserved mechanism that regulates a variety of cellular processes ranging from transcription control to signaling. In mitochondria, the inner membrane rhomboid protease PARL has been implicated in the control of life span and apoptosis by a so far uncharacterized mechanism. Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. As targeting of this precursor to the outer mitochondrial membrane has been shown to trigger mitophagy, we suggest that the PARL-catalyzed removal of the Pink1 signal sequence in the canonical import pathway acts as a cellular checkpoint for mitochondrial integrity. Furthermore, we show that two Parkinson's disease-causing mutations decrease the processing of Pink1 by PARL, with attendant implications for pathogenesis.
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, Heidelberg, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Meissner
authors.forename: Holger
authors.initials: H
authors.lastname: Lorenz
authors.forename: Andreas
authors.initials: A
authors.lastname: Weihofen
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D002254:Carbonates / Q000737:chemistry; D002460:Cell Line; D004734:Energy Metabolism / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D045726:Metalloproteases / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010447:Peptide Hydrolases / Q000737:chemistry; D010957:Plasmids / Q000235:genetics; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002254:Carbonates; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D010447:Peptide Hydrolases; D011494:Protein Kinases; D034741:RNA, Small Interfering; D000099202:PTEN-Induced Putative Kinase; C005686:sodium carbonate; C485223:PARL protein, human