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

• Verfasst von: Niemeyer, Johannes [VerfasserIn]
• Verfasst von: Heidasch, Ronny [VerfasserIn]
• Verfasst von: Dederer, Verena [VerfasserIn]
• Verfasst von: Lemberg, Marius [VerfasserIn]
• Titel: The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban
• Verf.angabe: Johannes Niemeyer, Torben Mentrup, Ronny Heidasch, Stephan A. Müller, Uddipta Biswas, Rieke Meyer, Alkmini A. Papadopoulou, Verena Dederer, Martina Haug‐Kröper, Vivian Adamski, Renate Lüllmann‐Rauch, Martin Bergmann, Artur Mayerhofer, Paul Saftig, Gunther Wennemuth, Rolf Jessberger, Regina Fluhrer, Stefan F. Lichtenthaler, Marius K. Lemberg & Bernd Schröder
• E-Jahr: 2019
• Jahr: [01 March 2019]
• Illustrationen: Illustrationen
• Fussnoten: Published online: February 7, 2019 ; Gesehen am 12.06.2019
• Titel Quelle: Enthalten in: European Molecular Biology OrganizationEMBO reports
• Ort Quelle: Heidelberg : EMBO Press, 2000
• Jahr Quelle: 2019
• Band/Heft Quelle: Volume 20, Issue 3 (2019) Artikel-Nummer e46449, Seite 1-20, 20 Seiten
• ISSN Quelle: 1469-3178
• DOI: doi:10.15252/embr.201846449
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: intramembrane proteolysis
• Sach-SW: phospholamban
• Sach-SW: signal peptide peptidase‐like proteases
• Sach-SW: spermatogenesis
• Sach-SW: tail‐anchored proteins
• K10plus-PPN: 1667294326

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. - See also: AA Papadopoulou et al (March 2019) and HS Young & MJ Lemieux (March 2019) - Synopsis - - <img class="highwire-embed" alt="Embedded Image" src="http://embor.embopress.org/sites/default/files/highwire/embor/20/3/e46449/embed/graphic-1.gif"/> - - The intramembrane protease SPPL2c is critical for the turnover of selected tail‐anchored proteins in spermatids and thereby supports differentiation and function of male germ cells. - - The presenilin‐homologue Signal peptide peptidase‐like 2c is an ER‐resident intramembrane protease endogenously expressed in murine and human spermatids.SPPL2c processes selected tail‐anchored proteins with a substrate spectrum distinct from that of Signal peptide peptidase (SPP).SPPL2c‐deficient mice show a partial loss of elongated spermatids and reduced motility of mature spermatozoa.Phospholamban represents a physiological SPPL2c substrate in murine testis.