SPPL2c, a member of the signal peptide peptidase (SPP)-like (SPPL) family of intramembrane aspartyl proteases, has been shown to have several important functions. It selectively cleaves transmembrane domains in type II orientation and is associated with multiple biological pathways [2,3,5,6]. Its functions range from being involved in male germ cell development to having potential roles in cell signaling, vesicular transport, and calcium regulation [1,2,4]. Genetic models, such as knockout mouse models, have been crucial in understanding its physiological functions [1,3].

In mice, SPPL2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, though fertility is preserved. Matings of male and female SPPL2c-/-mice result in reduced litter sizes. Proteomics identified phospholamban (PLN), a regulator of sarco/endoplasmic reticulum Ca2 + -ATPase (SERCA2), as a physiological SPPL2c substrate. The accumulation of PLN in elongated spermatids of SPPL2c-/-mice correlates with decreased intracellular Ca2 + levels, contributing to compromised male germ cell differentiation and function [1]. Additionally, SPPL2c was found to be catalytically active, with many of its candidate substrates clustering in the biological process of vesicular trafficking. It cleaves SNARE proteins, impairing vesicular transport and disturbing the integrity of subcellular compartments, which may suggest its involvement in acrosome formation during spermatogenesis [4].

In conclusion, SPPL2c plays a significant role in male germ cell development, likely through its proteolytic activity on substrates like PLN and its impact on vesicular transport. The use of SPPL2c knockout mouse models has provided valuable insights into its functions in male reproductive processes, highlighting its importance in understanding male fertility and associated biological mechanisms [1,4].

References:

1. Niemeyer, Johannes, Mentrup, Torben, Heidasch, Ronny, Lemberg, Marius K, Schröder, Bernd. 2019. The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. In EMBO reports, 20, . doi:10.15252/embr.201846449. https://pubmed.ncbi.nlm.nih.gov/30733280/

2. Papadopoulou, Alkmini A, Fluhrer, Regina. 2020. Signaling Functions of Intramembrane Aspartyl-Proteases. In Frontiers in cardiovascular medicine, 7, 591787. doi:10.3389/fcvm.2020.591787. https://pubmed.ncbi.nlm.nih.gov/33381526/

3. Mentrup, Torben, Cabrera-Cabrera, Florencia, Fluhrer, Regina, Schröder, Bernd. 2020. Physiological functions of SPP/SPPL intramembrane proteases. In Cellular and molecular life sciences : CMLS, 77, 2959-2979. doi:10.1007/s00018-020-03470-6. https://pubmed.ncbi.nlm.nih.gov/32052089/

4. Papadopoulou, Alkmini A, Müller, Stephan A, Mentrup, Torben, Lichtenthaler, Stefan F, Fluhrer, Regina. 2019. Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins. In EMBO reports, 20, . doi:10.15252/embr.201846451. https://pubmed.ncbi.nlm.nih.gov/30733281/

5. Voss, Matthias, Schröder, Bernd, Fluhrer, Regina. . Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases. In Biochimica et biophysica acta, 1828, 2828-39. doi:10.1016/j.bbamem.2013.03.033. https://pubmed.ncbi.nlm.nih.gov/24099004/

6. Mentrup, Torben, Loock, Ann-Christine, Fluhrer, Regina, Schröder, Bernd. 2017. Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets? In Biochimica et biophysica acta. Molecular cell research, 1864, 2169-2182. doi:10.1016/j.bbamcr.2017.06.007. https://pubmed.ncbi.nlm.nih.gov/28624439/