The clavesin family, neuron-specific lipid- and clathrin-binding Sec14 proteins regulating lysosomal morphology.
Clathrin-coated vesicles (CCVs) originating from the trans-Golgi network (TGN) provide a major transport pathway from the secretory system to endosomes/lysosomes. Herein we describe paralogous Sec14 domain-bearing proteins, clavesin 1/CRALBPL and clavesin 2, identified through a proteomic analysis of CCVs. Clavesins are enriched on CCVs and form a complex with clathrin heavy chain (CHC) and adaptor protein-1, major coat components of TGN-derived CCVs. The proteins co-localize with markers of endosomes and the TGN as well as with CHC and adaptor protein-1. A membrane mimic assay using the Sec14 domain of clavesin 1 reveals phosphatidylinositol 3,5-bisphosphate as a specific lipid partner. Phosphatidylinositol 3,5-bisphosphate is localized to late endosomes/lysosomes, and interestingly, isoform-specific knockdown of clavesins in neurons using lentiviral delivery of interfering RNA leads to enlargement of a lysosome-associated membrane protein 1-positive membrane compartment with no obvious influence on the CCV machinery at the TGN. Since clavesins are expressed exclusively in neurons, this new protein family appears to provide a unique neuron-specific regulation of late endosome/lysosome morphology.
Katoh
Yohei
Y
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Ritter
Brigitte
B
Gaffry
Thomas
T
Blondeau
Francois
F
Höning
Stefan
S
McPherson
Peter S
PS
D033961:Adaptor Protein Complex 1 / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009928:Organ Specificity; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D021601:trans-Golgi Network / Q000378:metabolism
D033961:Adaptor Protein Complex 1; C529460:CLVS1 protein, human; D002352:Carrier Proteins; D002966:Clathrin; D052118:Lysosomal-Associated Membrane Protein 1; D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate