title: FKBP8 recruits LC3A to mediate Parkin-independent mitophagy.
abstract: Mitophagy, the selective removal of damaged or excess mitochondria by autophagy, is an important process in cellular homeostasis. The outer mitochondrial membrane (OMM) proteins NIX, BNIP3, FUNDC1, and Bcl2-L13 recruit ATG8 proteins (LC3/GABARAP) to mitochondria during mitophagy. FKBP8 (also known as FKBP38), a unique member of the FK506-binding protein (FKBP) family, is similarly anchored in the OMM and acts as a multifunctional adaptor with anti-apoptotic activity. In a yeast two-hybrid screen, we identified FKBP8 as an ATG8-interacting protein. Here, we map an N-terminal LC3-interacting region (LIR) motif in FKBP8 that binds strongly to LC3A bothin vitroandin vivoFKBP8 efficiently recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner. The mitophagy receptors BNIP3 and NIX in contrast are unable to mediate an efficient recruitment of LC3A even after mitochondrial damage. Co-expression of FKBP8 with LC3A profoundly induces Parkin-independent mitophagy. Strikingly, even when acting as a mitophagy receptor, FKBP8 avoids degradation by escaping from mitochondria. In summary, this study identifies novel roles for FKBP8 and LC3A, which act together to induce mitophagy.
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Zambarlal
authors.initials: Z
authors.lastname: Bhujabal
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Birgisdottir
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Eva
authors.initials: E
authors.lastname: Sjøttem
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Hanne B
authors.initials: HB
authors.lastname: Brenne
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Aud
authors.initials: A
authors.lastname: Øvervatn
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Habisov
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kirkin
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
authors.forename: Trond
authors.initials: T
authors.lastname: Lamark
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway terje.johansen@uit.no.
authors.forename: Terje
authors.identifier: 0000-0003-1451-9578
authors.initials: T
authors.lastname: Johansen
mesh_terms: D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C000595707:BCL2 protein, human; C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; C471205:FKBP8 protein, human; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D022021:Tacrolimus Binding Proteins
keywords: FKBP38; FKBP8; LC3A; autophagy; mitophagy