TY  - JOUR
AU  - Niemeyer, Johannes
AU  - Mentrup, Torben
AU  - Heidasch, Ronny
AU  - Müller, Stephan A
AU  - Biswas, Uddipta
AU  - Meyer, Rieke
AU  - Papadopoulou, Alkmini A
AU  - Dederer, Verena
AU  - Haug-Kröper, Martina
AU  - Adamski, Vivian
AU  - Lüllmann-Rauch, Renate
AU  - Bergmann, Martin
AU  - Mayerhofer, Artur
AU  - Saftig, Paul
AU  - Wennemuth, Gunther
AU  - Jessberger, Rolf
AU  - Fluhrer, Regina
AU  - Lichtenthaler, Stefan F
AU  - Lemberg, Marius K
AU  - Schröder, Bernd
TI  - The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.
JO  - EMBO reports
VL  - 20
IS  - 3
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-06926
SP  - e46449
PY  - 2019
AB  - 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.
KW  - Amino Acid Sequence
KW  - Animals
KW  - Aspartic Acid Endopeptidases: chemistry
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Calcium: metabolism
KW  - Calcium-Binding Proteins: metabolism
KW  - Cell Membrane: enzymology
KW  - Endoplasmic Reticulum: metabolism
KW  - Female
KW  - Germ Cells: metabolism
KW  - HEK293 Cells
KW  - HeLa Cells
KW  - Homeostasis
KW  - Humans
KW  - Male
KW  - Membrane Proteins: chemistry
KW  - Membrane Proteins: metabolism
KW  - Mice
KW  - Organ Specificity
KW  - Spermatids: metabolism
KW  - Substrate Specificity
KW  - Testis: enzymology
LB  - PUB:(DE-HGF)16
C6  - pmid:30733280
C2  - pmc:PMC6399600
DO  - DOI:10.15252/embr.201846449
UR  - https://pub.dzne.de/record/140604
ER  -