Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins

Redpath, GMI; Sophocleous, RA; Turnbull, L; Whitchurch, CB; Cooper, ST

Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins

Redpath, GMI Sophocleous, RA Turnbull, L

Whitchurch, CB

Cooper, ST

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Publication Type:: Journal Article
Citation:: Traffic, 2016, 17 (3), pp. 245 - 266
Issue Date:: 2016-03-01

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Field	Value	Language
dc.contributor.author	Redpath, GMI	en_US
dc.contributor.author	Sophocleous, RA	en_US
dc.contributor.author	Turnbull, L https://orcid.org/0000-0002-9255-9033	en_US
dc.contributor.author	Whitchurch, CB https://orcid.org/0000-0003-2296-3791	en_US
dc.contributor.author	Cooper, ST	en_US
dc.date.available	2020-05-25T19:28:27Z
dc.date.issued	2016-03-01	en_US
dc.identifier.citation	Traffic, 2016, 17 (3), pp. 245 - 266	en_US
dc.identifier.issn	1398-9219	en_US
dc.identifier.uri	http://hdl.handle.net/10453/41536
dc.description.abstract	© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Ferlins are an ancient family of Ca2+-binding, multi-C2 domain vesicle fusion proteins. Of the six human ferlins, mutations in dysferlin cause muscular dystrophy and otoferlin cause deafness. We detail the tissue-distribution, subcellular localization and endocytic trafficking of the human ferlins. Dysferlin and myoferlin, type-I ferlins, localize to the plasma membrane and late endosomes, which display potential for occasional recycling. Otoferlin and Fer1L6, type-II ferlins, localize to dedicated recycling subcompartments of the trans-Golgi network. We establish that type-I and type-II ferlins segregate into late-endosomal and recycling trans-Golgi compartments. Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca2+-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 Ca2+-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca2+-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.	en_US
dc.relation	http://purl.org/au-research/grants/arc/LE0989920
dc.relation.ispartof	Traffic	en_US
dc.relation.isbasedon	10.1111/tra.12370	en_US
dc.subject.classification	Developmental Biology	en_US
dc.subject.mesh	Pancreas	en_US
dc.subject.mesh	Brain	en_US
dc.subject.mesh	COS Cells	en_US
dc.subject.mesh	Cell Membrane	en_US
dc.subject.mesh	Endosomes	en_US
dc.subject.mesh	trans-Golgi Network	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Cercopithecus aethiops	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	rab GTP-Binding Proteins	en_US
dc.subject.mesh	Calcium-Binding Proteins	en_US
dc.subject.mesh	Muscle Proteins	en_US
dc.subject.mesh	Membrane Proteins	en_US
dc.subject.mesh	Organ Specificity	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Protein Transport	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.subject.mesh	HEK293 Cells	en_US
dc.subject.mesh	Chlorocebus aethiops	en_US
dc.title	Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	17	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1108 Medical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	open_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	17	en_US

Abstract:

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Ferlins are an ancient family of Ca2+-binding, multi-C2 domain vesicle fusion proteins. Of the six human ferlins, mutations in dysferlin cause muscular dystrophy and otoferlin cause deafness. We detail the tissue-distribution, subcellular localization and endocytic trafficking of the human ferlins. Dysferlin and myoferlin, type-I ferlins, localize to the plasma membrane and late endosomes, which display potential for occasional recycling. Otoferlin and Fer1L6, type-II ferlins, localize to dedicated recycling subcompartments of the trans-Golgi network. We establish that type-I and type-II ferlins segregate into late-endosomal and recycling trans-Golgi compartments. Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca2+-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 Ca2+-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca2+-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.

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http://hdl.handle.net/10453/41536