title: SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways.
abstract: The FERM-like domain-containing sorting nexins of the SNX17/SNX27/SNX31 family have been proposed to mediate retrieval of transmembrane proteins from the lysosomal pathway. In this paper, we describe a stable isotope labeling with amino acids in culture-based quantitative proteomic approach that allows an unbiased, global identification of transmembrane cargoes that are rescued from lysosomal degradation by SNX17. This screen revealed that several integrins required SNX17 for their stability, as depletion of SNX17 led to a loss of β1 and β5 integrins and associated a subunits from HeLa cells as a result of increased lysosomal degradation. SNX17 bound to the membrane distal NPXY motif in β integrin cytoplasmic tails, thereby preventing lysosomal degradation of β integrins and their associated a subunits. Furthermore, SNX17-dependent retrieval of integrins did not depend on the retromer complex. Consistent with an effect on integrin recycling, depletion of SNX17 also caused alterations in cell migration. Our data provide mechanistic insight into the retrieval of internalized integrins from the lysosomal degradation pathway, a prerequisite for subsequent recycling of these matrix receptors.
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Steinberg
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Heesom
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bass
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
mesh_terms: D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D040901:Proteomics; D034622:RNA Interference; D034741:RNA, Small Interfering; D058305:Sorting Nexins / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D039641:Integrin beta Chains; D019012:Integrin beta1; D034741:RNA, Small Interfering; C487895:SNX17 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; C084344:integrin beta5