Regulating the regulator: intramembrane proteolysis of vesicular trafficking proteins and the SERCA regulator phospholamban

Abstract

Intramembrane proteases reside within the subcellular compartments of cells to carry out a multiplicity of functions. One such family is the signal peptide peptidase (SPP) and signal peptide peptidase‐like (SPPL) family. The SPP/SPPL family comprises several homologs of aspartyl‐intramembrane proteases, and recent studies demonstrate distinct compartmentalization for each and a largely unknown cadre of substrates. Due to their hydrophobic nature, identification of substrates for intramembrane proteases can be an arduous task. In this issue of EMBO Reports, two studies identify physiological substrates of SPPL2c (1, 2). SPPL2c targets a variety of SNARE proteins, thereby playing a significant role in vesicular transport from the ER and in turn influencing the composition of the Golgi. Furthermore, trafficking defects observed in SPPL2c lacking cells lead to morphological changes in the spermatid cells of the testes, the only known site of protein expression. In these cells, phospholamban, a single‐pass transmembrane regulator of the Ca²⁺ transporter SERCA, was also identified as an SPPL2c substrate that impacts Ca²⁺ storage. This may explain the SPPL2c effect on germ cell development.

Figure 1. Distinct intramembrane proteases are located in the ER (SPP and SPPL2c) and the Golgi (SPPL3)

The SPPL2c, localized to the ER, has been shown to cleave substrates that include SNARE family members involved in vesicle fusion, and phospholamban important in Ca²⁺ regulation. SPPL2c plays a role in clearing these substrates, resulting in decreased vesicle fusion, a decrease in the transfer of glycosyltransferases (GT) to the Golgi, and a decreased presence of SPPL3 in the Golgi; all factors required for the development of strong healthy sperm. A loss of SPPL2c results in substrate accumulation and the development of less healthy sperm, suggesting that normal vesicular trafficking is not desired in the developing spermatid and defects lead to reduced sperm motility.