title: Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins.
abstract: Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca(2+)-regulated phospholipid-binding domains that regulate vesicle fusion in the synaptotagmin family. In humans, dysferlin mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca(2+)-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca(2+)-triggered auditory neurotransmission. In this study, we describe the tissue-specific expression, subcellular localization and endocytic trafficking of the ferlin family. Studies of endosomal transit together with 3D-structured illumination microscopy reveals dysferlin and myoferlin are abundantly expressed at the PM and cycle to Rab7-positive late endosomes, supporting potential roles in the late-endosomal pathway. In contrast, Fer1L6 shows concentrated localization to a specific compartment of the trans-Golgi/recycling endosome, cycling rapidly between this compartment and the PM via Rab11 recycling endosomes. Otoferlin also shows trans-Golgi to PM cycling, with very low levels of PM otoferlin suggesting either brief PM residence, or rare incorporation of otoferlin molecules into the PM. Thus, type-I and type-II ferlins segregate as PM/late-endosomal or trans-Golgi/recycling ferlins, consistent with different ferlins mediating vesicle fusion events in specific subcellular locations.
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Gregory M I
authors.initials: GM
authors.lastname: Redpath
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Reece A
authors.initials: RA
authors.lastname: Sophocleous
authors.affiliation: Microbial Imaging Facility, The iThree Institute, University of Technology Sydney, Ultimo, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.affiliation: Microbial Imaging Facility, The iThree Institute, University of Technology Sydney, Ultimo, Australia.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; C118457:OTOF protein, human; D020691:rab GTP-Binding Proteins
keywords: Fer1L4; Fer1L5; Fer1L6; Rab7; dysferlin; late endosome; myoferlin; otoferlin; recycling endosome; trans-Golgi