Journal Article

DZNE-2020-06926

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

Niemeyer, J. ; Mentrup, T. ; Heidasch, R. ; Müller, S. A.DZNE* ; Biswas, U. ; Meyer, R. ; Papadopoulou, A. A. ; Dederer, V. ; Haug-Kröper, M. ; Adamski, V. ; Lüllmann-Rauch, R. ; Bergmann, M. ; Mayerhofer, A. ; Saftig, P. ; Wennemuth, G. ; Jessberger, R. ; Fluhrer, R.DZNE* ; Lichtenthaler, S. F.DZNE* ; Lemberg, M. K. ; Schröder, B. (Corresponding author)

2019
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embr.201846449

Abstract: 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 Ca2+-ATPase (SERCA2)-regulating protein phospholamban (PLN) as a physiological SPPL2c substrate. Accumulation of PLN correlates with a decrease in intracellular Ca2+ levels in elongated spermatids that likely contribute to the compromised male germ cell differentiation and function of SPPL2c-/- mice.

Keyword(s): Amino Acid Sequence (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: chemistry (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Calcium: metabolism (MeSH) ; Calcium-Binding Proteins: metabolism (MeSH) ; Cell Membrane: enzymology (MeSH) ; Endoplasmic Reticulum: metabolism (MeSH) ; Female (MeSH) ; Germ Cells: metabolism (MeSH) ; HEK293 Cells (MeSH) ; HeLa Cells (MeSH) ; Homeostasis (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Membrane Proteins: chemistry (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Organ Specificity (MeSH) ; Spermatids: metabolism (MeSH) ; Substrate Specificity (MeSH) ; Testis: enzymology (MeSH)

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)
2. Signal Peptide Peptidases as Models for γ-Secretase (AG Fluhrer)
3. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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