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.

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

“…More recently, there have been reports of three-way co-expression of SERCA, SLN, and PLN together, as assessed at the single-cell level, in human leg postural muscle (vastus lateralis) and Takotsubo cardiomyopathy patients (left ventricle), with enhanced SERCA inhibition (27,142). These results support MacLennan's early prediction of 'superinhibitory' trimeric complexes comprised of one catalytic pump (SERCA) and two inhibitory subunits (SLN and PLN) expressed in native muscle and heart (71,143), as assessed in cell culture models with epitope-tagged peptide regulators, which have received the newly appropriate family terminology as "regulins" (133,144). As such, it is becoming clear that SERCA and its regulatory peptides are expressed broadly in tissue-specific patterns, with concomitant single and dual physiological coupling to SERCA (27,70,113,143).…”

“…Thus, we propose that horse SLN inhibition is not regulated in the short-term by post-translational modification. We also propose that the potency of SLN inhibition of SERCA in horse muscles and heart chambers depends on the relative expression level of SLN and SERCA proteins, which are likely regulated temporally through cellular mechanistic checkpoints such as transcription, translation, and degradation (133)(134)(135).…”

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

“…These results support MacLennan’s seminal report of “super-inhibitory” trimeric complexes comprising one catalytic pump (SERCA) and two inhibitory subunits (SLN and PLN), proposed to be expressed in native muscle and heart [ 105 , 106 ], as initially assessed via cell culture and mouse models of epitope-tagged peptide regulators. As additional peptide regulators of SERCA continue to be identified, the gene/peptide family has been termed “regulins” [ 13 , 82 , 103 , 107 , 108 ].…”

“…In the heart, PLN peptides are reported to be selectively degraded (relative to SERCA proteins) by a metformin-induced ubiquitin-mediated pathway and a phosphorylation-induced autophagy-mediated pathway [ 125 , 126 ]. In testes, PLN peptides are reported to be degraded by intramembrane proteolysis [ 108 , 127 ]. Thus, it is possible that horse muscle utilizes similar mechanism(s) for robust degradation of SLN peptides that are translated from the abundant level of SLN RNA transcripts.…”