title: NOA1, a novel ClpXP substrate, takes an unexpected nuclear detour prior to mitochondrial import.
abstract: The mitochondrial matrix GTPase NOA1 is a nuclear encoded protein, essential for mitochondrial protein synthesis, oxidative phosphorylation and ATP production. Here, we demonstrate that newly translated NOA1 protein is imported into the nucleus, where it localizes to the nucleolus and interacts with UBF1 before nuclear export and import into mitochondria. Mutation of the nuclear localization signal (NLS) prevented both nuclear and mitochondrial import while deletion of the N-terminal mitochondrial targeting sequence (MTS) or the C-terminal RNA binding domain of NOA1 impaired mitochondrial import. Absence of the MTS resulted in accumulation of NOA1 in the nucleus and increased caspase-dependent apoptosis. We also found that export of NOA1 from the nucleus requires a leptomycin-B sensitive, Crm1-dependent nuclear export signal (NES). Finally, we show that NOA1 is a new substrate of the mitochondrial matrix protease complex ClpXP. Our results uncovered an unexpected, mandatory detour of NOA1 through the nucleolus before uptake into mitochondria. We propose that nucleo-mitochondrial translocation of proteins is more widespread than previously anticipated providing additional means to control protein bioavailability as well as cellular communication between both compartments.
authors: Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Natalie
authors: N
authors: Al-Furoukh
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, Boston, Massachusetts, United States of America.
authors: Julia R
authors: JR
authors: Kardon
authors: Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Marcus
authors: M
authors: Krüger
authors: Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Marten
authors: M
authors: Szibor
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, Boston, Massachusetts, United States of America.
authors: Tania A
authors: TA
authors: Baker
authors: Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Thomas
authors: T
authors: Braun
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D049071:Endopeptidase Clp / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D012313:RNA / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D005231:Fatty Acids, Unsaturated; D019913:Nuclear Localization Signals; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D012313:RNA; D006160:Guanosine Triphosphate; D004247:DNA; D049071:Endopeptidase Clp; D020558:GTP Phosphohydrolases; C038753:leptomycin B