title: Calsyntenins mediate TGN exit of APP in a kinesin-1-dependent manner.
abstract: Kinesin motors are required for the export of membranous cargo from the trans-Golgi network (TGN), yet information about how kinesins are recruited to forming transport intermediates is sparse. Here we show that the Kinesin-1 docking protein calsyntenin-1 localizes to the TGN in vivo and directly and specifically recruits Kinesin-1 to Golgi/TGN membranes as well as to dynamic post-Golgi carriers. Overexpression of various calsyntenin chimeras and kinesin light chain 1 (KLC1) at high levels caused the formation of aberrant membrane stacks at the endoplasmic reticulum (ER) or the Golgi, disrupted overall Golgi structure and blocked exit of calsyntenin from the TGN. Intriguingly, this blockade of calsyntenin exit strongly and selectively impeded TGN exit of amyloid precursor protein (APP). Using live cell microscopy we found that calsyntenins exit the TGN in Kinesin-1-decorated tubular structures which may serve as carriers for calsyntenin-1-mediated post-TGN transport of APP. Abrogation of this pathway via virus-mediated knockdown of calsyntenin-1 expression in primary cultured neurons caused a marked elevation of APP C-terminal fragments. Together, these results indicate a role for calsyntenin-1 in Kinesin-1-dependent TGN exit and post-Golgi transport of APP-containing organelles and further suggest that distinct intracellular routes may exhibit different capacities for proteolytic processing of APP.
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ludwig
authors.forename: Jessica
authors.initials: J
authors.lastname: Blume
authors.forename: Tu-My
authors.initials: TM
authors.lastname: Diep
authors.forename: Ju
authors.initials: J
authors.lastname: Yuan
authors.forename: José María
authors.initials: JM
authors.lastname: Mateos
authors.forename: Kerstin
authors.initials: K
authors.lastname: Leuthäuser
authors.forename: Martin
authors.initials: M
authors.lastname: Steuble
authors.forename: Peter
authors.initials: P
authors.lastname: Streit
authors.forename: Peter
authors.initials: P
authors.lastname: Sonderegger
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism* / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; C000715688:KLC1 protein, human; D016547:Kinesins