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EMBO Rep. 2019 Mar;20(3). pii: e46451. doi: 10.15252/embr.201846451. Epub 2019 Feb 7.

Signal Peptide Peptidase-Like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins.

Author information

1
Institute for Metabolic Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University Munich, Munich, Germany.
2
DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
3
Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
4
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
5
Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, and Institute for Advanced Study, Technical University Munich, Munich, Germany.
6
Max Planck Institute of Biochemistry, Martinsried, Germany.
7
Cell Biology, Anatomy III, Biomedical Center (BMC), Ludwig-Maximilians University Munich, Munich, Germany.
8
Institute for Diabetes and Obesity, Monoclonal Antibody Core Facility, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
9
Munich Center for Systems Neurology (SyNergy), Munich, Germany.
10
Institute for Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
11
Institute for Metabolic Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University Munich, Munich, Germany regina.fluhrer@med.uni-muenchen.de.

Abstract

Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development of pathologies, such as Alzheimer's disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis.

KEYWORDS:

SNARE; SPP/SPPL‐family; glycosyltransferases; intramembrane proteases; spermatogenesis

PMID:
30733281
DOI:
10.15252/embr.201846451

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