Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation

EMBO J. 2014 Dec 17;33(24):2890-905. doi: 10.15252/embj.201488375.

Matthias Voss ¹, Ulrike Künzel ¹, Fabian Higel ², Peer-Hendrik Kuhn ³, Alessio Colombo ⁴, Akio Fukumori ⁴, Martina Haug-Kröper ¹, Bärbel Klier ⁴, Gudula Grammer ¹, Andreas Seidl ², Bernd Schröder ⁵, Reinhard Obst ⁶, Harald Steiner ⁷, Stefan F Lichtenthaler ⁸, Christian Haass ⁹, Regina Fluhrer ¹⁰

Affiliations

1 Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
2 Sandoz Biopharmaceuticals/HEXAL AG, Oberhaching, Germany.
3 DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Institute for Advanced Study, Technische Universität München, Garching, Germany.
4 DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
5 Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
6 Institute for Immunology, Ludwig-Maximilians University Munich, Munich, Germany.
7 Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
8 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.
9 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.
10 Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany [email protected].

PMID: 25354954 DOI: 10.15252/embj.201488375

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.

Keywords

GxGD aspartyl proteases; glycosyltransferases; protein glycosylation; signal peptide peptidase like‐3.

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