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Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.

Abstract (Expand)

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.

Authors: A. A. Papadopoulou, S. A. Muller, T. Mentrup, M. D. Shmueli, J. Niemeyer, M. Haug-Kroper, J. von Blume, A. Mayerhofer, R. Feederle, B. Schroder, S. F. Lichtenthaler, R. Fluhrer

Date Published: 9th Feb 2019

Publication Type: Journal

The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

Abstract (Expand)

Signal peptide peptidase (SPP) and the four homologous SPP-like (SPPL) proteases constitute a family of intramembrane aspartyl proteases with selectivity for type II-oriented transmembrane segments. … Here, we analyse the physiological function of the orphan protease SPPL2c, previously considered to represent a non-expressed pseudogene. We demonstrate proteolytic activity of SPPL2c towards selected tail-anchored proteins. Despite shared ER localisation, SPPL2c and SPP exhibit distinct, though partially overlapping substrate spectra and inhibitory profiles, and are organised in different high molecular weight complexes. Interestingly, SPPL2c is specifically expressed in murine and human testis where it is primarily localised in spermatids. In mice, SPPL2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, but preserved fertility. However, matings of male and female SPPL2c(-/-) mice exhibit reduced litter sizes. Using proteomics we identify the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2)-regulating protein phospholamban (PLN) as a physiological SPPL2c substrate. Accumulation of PLN correlates with a decrease in intracellular Ca(2+) levels in elongated spermatids that likely contribute to the compromised male germ cell differentiation and function of SPPL2c(-/-) mice.

Authors: J. Niemeyer, T. Mentrup, R. Heidasch, S. A. Muller, U. Biswas, R. Meyer, A. A. Papadopoulou, V. Dederer, M. Haug-Kroper, V. Adamski, R. Lullmann-Rauch, M. Bergmann, A. Mayerhofer, P. Saftig, G. Wennemuth, R. Jessberger, R. Fluhrer, S. F. Lichtenthaler, M. K. Lemberg, B. Schroder

Date Published: 9th Feb 2019

Publication Type: Journal

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