Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Signal Peptide Peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins

EMBO Rep. 2019 May;20(5). pii: e48133

Authors/Editors: Alkmini A Papadopoulou
Stephan A Müller
Torben Mentrup
Merav D Shmueli
Johannes Niemeyer
Martina Haug-Kröper
Julia von Blume
Artur Mayerhofer
Regina Feederle
Bernd Schröder
Stefan F Lichtenthaler
Regina Fluhrer
Publication Date: 2019
Type of Publication: Journal Article

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.

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