title: Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation.
abstract: Protein N-glycosylation is involved in a variety of physiological and pathophysiological processes such as autoimmunity, tumour progression and metastasis. Signal peptide peptidase-like 3 (SPPL3) is an intramembrane-cleaving aspartyl protease of the GxGD type. Its physiological function, however, has remained enigmatic, since presently no physiological substrates have been identified. We demonstrate that SPPL3 alters the pattern of cellular N-glycosylation by triggering the proteolytic release of active site-containing ectodomains of glycosidases and glycosyltransferases such as N-acetylglucosaminyltransferase V, β-1,3 N-acetylglucosaminyltransferase 1 and β-1,4 galactosyltransferase 1. Cleavage of these enzymes leads to a reduction in their cellular activity. In line with that, reduced expression of SPPL3 results in a hyperglycosylation phenotype, whereas elevated SPPL3 expression causes hypoglycosylation. Thus, SPPL3 plays a central role in an evolutionary highly conserved post-translational process in eukaryotes.
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Voss
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Künzel
authors.affiliation: Sandoz Biopharmaceuticals/HEXAL AG, Oberhaching, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Higel
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Institute for Advanced Study, Technische Universität München, Garching, Germany.
authors.forename: Peer-Hendrik
authors.initials: PH
authors.lastname: Kuhn
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Haug-Kröper
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Klier
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Gudula
authors.initials: G
authors.lastname: Grammer
authors.affiliation: Sandoz Biopharmaceuticals/HEXAL AG, Oberhaching, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Seidl
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
authors.affiliation: Institute for Immunology, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Obst
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany rfluhrer@med.uni-muenchen.de.
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006026:Glycoside Hydrolases / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism*; D006801:Humans; D011134:Polysaccharides / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D011134:Polysaccharides; D016695:Glycosyltransferases; D006026:Glycoside Hydrolases; D016282:Aspartic Acid Endopeptidases; C513914:signal peptide peptidase like 3, human
keywords: GxGD aspartyl proteases; glycosyltransferases; protein glycosylation; signal peptide peptidase like‐3