title: SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling.
abstract: Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stendel
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.forename: Henning
authors.initials: H
authors.lastname: Kleine
authors.forename: Estelle
authors.initials: E
authors.lastname: Arnaud
authors.forename: Murat
authors.initials: M
authors.lastname: Ozçelik
authors.forename: Páris N M
authors.initials: PN
authors.lastname: Sidiropoulos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zenker
authors.forename: Fanny
authors.initials: F
authors.lastname: Schüpfer
authors.forename: Ute
authors.initials: U
authors.lastname: Lehmann
authors.forename: Radoslaw M
authors.initials: RM
authors.lastname: Sobota
authors.forename: David W
authors.initials: DW
authors.lastname: Litchfield
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism*; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C552538:Sh3tc2 protein, mouse; C552539:Sh3tc2 protein, rat