title: O-glycosylation regulates polarized secretion by modulating Tango1 stability.
abstract: Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.
authors.affiliation: Developmental Glycobiology Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370;
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, Institute of Biomedicine.
authors.forename: Zulfeqhar Ali
authors.initials: ZA
authors.lastname: Syed
authors.affiliation: Institute of Health and Care Sciences, University of Gothenburg, SE-405 30 Gothenburg, Sweden;
authors.forename: Iris
authors.initials: I
authors.lastname: van Dijk Härd
authors.affiliation: Department of Chemistry, Changwon National University, Changwon, Gyeongnam 641-773, South Korea; andDepartment of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602-4712.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602-4712.
authors.forename: Lance
authors.initials: L
authors.lastname: Wells
authors.affiliation: Developmental Glycobiology Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370; Kelly.Tenhagen@nih.gov.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Ten Hagen
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D002114:Calcinosis; D002384:Catalysis; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D009077:Mucins / Q000378:metabolism; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D013381:Subtilisins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D009077:Mucins; C109766:tgo protein, Drosophila; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C076273:dfurin2; D017350:N-Acetylgalactosaminyltransferases; C000589491:PGANT4 protein, Drosophila; D013381:Subtilisins
keywords: Drosophila; familial tumoral calcinosis; mucin; peritrophic membrane; proventriculus