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Identification of an endocytosis motif in an intracellular loop of Wntless, essential for its recycling and the control of Wnt signalling


Gasnereau, I; Herr, P; Chia, P Z C; Basler, K; Gleeson, P A (2011). Identification of an endocytosis motif in an intracellular loop of Wntless, essential for its recycling and the control of Wnt signalling. Journal of Biological Chemistry, 286(50):43324-43333.

Abstract

The secretion of Wnt signaling proteins is dependent upon a transmembrane sorting receptor, Wntless (Wls), which recycles between the trans-Golgi network (TGN) and the cell surface. Loss of Wls results in impairment of Wnt secretion and defects in development and homeostasis in Drosophila, C. elegans and the mouse. The sorting signals for the internalisation and trafficking of Wls have not been defined. Here we demonstrate that Wls internalisation requires clathrin and dynamin I, components of the clathrin mediated endocytosis pathway. Moreover, we have identified a conserved YXXϕ endocytosis motif in the third intracellular loop of the multi-pass membrane protein Wls. Mutation of the tyrosine-based motif YEGL to AEGL (Y425A) resulted in the accumulation of human mutant Wls on the cell surface of transfected HeLa cells. The cell surface accumulation of WlsAEGL was rescued by the insertion of a classical YXXϕ motif in the cytoplasmic tail. Significantly, a Drosophila WlsAEGL mutant displayed a wing notch phenotype, with reduced Wnt secretion and signalling. These findings demonstrate that YXXϕ endocytosis motifs can occur in the intracellular loops of multipass membrane proteins and, moreover, provide direct evidence that the trafficking of Wls is required for efficient secretion of Wnt signalling proteins.

The secretion of Wnt signaling proteins is dependent upon a transmembrane sorting receptor, Wntless (Wls), which recycles between the trans-Golgi network (TGN) and the cell surface. Loss of Wls results in impairment of Wnt secretion and defects in development and homeostasis in Drosophila, C. elegans and the mouse. The sorting signals for the internalisation and trafficking of Wls have not been defined. Here we demonstrate that Wls internalisation requires clathrin and dynamin I, components of the clathrin mediated endocytosis pathway. Moreover, we have identified a conserved YXXϕ endocytosis motif in the third intracellular loop of the multi-pass membrane protein Wls. Mutation of the tyrosine-based motif YEGL to AEGL (Y425A) resulted in the accumulation of human mutant Wls on the cell surface of transfected HeLa cells. The cell surface accumulation of WlsAEGL was rescued by the insertion of a classical YXXϕ motif in the cytoplasmic tail. Significantly, a Drosophila WlsAEGL mutant displayed a wing notch phenotype, with reduced Wnt secretion and signalling. These findings demonstrate that YXXϕ endocytosis motifs can occur in the intracellular loops of multipass membrane proteins and, moreover, provide direct evidence that the trafficking of Wls is required for efficient secretion of Wnt signalling proteins.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2011
Deposited On:07 Jan 2012 19:44
Last Modified:26 Aug 2016 07:32
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in Journal of Biological Chemistry.Gasnereau, I; Herr, P; Chia, P Z C; Basler, K; Gleeson, P A (2011). Identification of an endocytosis motif in an intracellular loop of Wntless, essential for its recycling and the control of Wnt signalling. Journal of Biological Chemistry, 286(50):43324-43333. © the American Society for Biochemistry and Molecular Biology. Gasnereau, I; Herr, P; Chia, P Z C; Basler, K; Gleeson, P A (2011). Identification of an endocytosis motif in an intracellular loop of Wntless, essential for its recycling and the control of Wnt signalling. Journal of Biological Chemistry, 286(50):43324-43333.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1074/jbc.M111.307231
PubMed ID:22027831
Permanent URL: http://doi.org/10.5167/uzh-53019

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