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The intramembrane protease SPPL 2c promotes male germ cell development by cleaving phospholamban
Author(s) -
Niemeyer Johannes,
Mentrup Torben,
Heidasch Ronny,
Müller Stephan A,
Biswas Uddipta,
Meyer Rieke,
Papadopoulou Alkmini A,
Dederer Verena,
HaugKröper Martina,
Adamski Vivian,
LüllmannRauch Renate,
Bergmann Martin,
Mayerhofer Artur,
Saftig Paul,
Wennemuth Gunther,
Jessberger Rolf,
Fluhrer Regina,
Lichtenthaler Stefan F,
Lemberg Marius K,
Schröder Bernd
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201846449
Subject(s) - phospholamban , proteases , endoplasmic reticulum , biology , microbiology and biotechnology , protease , germ cell , transmembrane protein , biochemistry , enzyme , gene , receptor
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 SPPL 2c, previously considered to represent a non‐expressed pseudogene. We demonstrate proteolytic activity of SPPL 2c towards selected tail‐anchored proteins. Despite shared ER localisation, SPPL 2c and SPP exhibit distinct, though partially overlapping substrate spectra and inhibitory profiles, and are organised in different high molecular weight complexes. Interestingly, SPPL 2c is specifically expressed in murine and human testis where it is primarily localised in spermatids. In mice, SPPL 2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, but preserved fertility. However, matings of male and female SPPL 2c −/− mice exhibit reduced litter sizes. Using proteomics we identify the sarco/endoplasmic reticulum Ca 2+ ‐ ATP ase ( SERCA 2)‐regulating protein phospholamban ( PLN ) as a physiological SPPL 2c 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 SPPL 2c −/− mice.