Physiological functions of SPP/SPPL intramembrane proteases

Abstract

Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.

Keywords: Intramembrane proteolysis; Membrane trafficking; Protein degradation; Signal peptide peptidase-like; Signal transduction; γ-secretase.

Fig. 1

Major cleavage modes of SPP/SPPL proteases. Summary of the current state of knowledge of accepted substrate types and the major different modes of substrate cleavage by signal peptide peptidase (SPP) and the four SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3

Fig. 2

Mechanisms of signal transduction regulation by SPP/SPPL proteases. a SPP/SPPL proteases can transduce intracellular signals by releasing an intracellular domain (ICD) which either acts as transcription factor itself or is able to exert an impact on gene expression by interaction with the transcriptional machinery. b As exemplified by processing of CD74, SPP/SPPL proteases can cleave regulatory components of signalling pathways. The N-terminal fragment (NTF) of CD74 (depicted in blue) has the capability to influence subcellular trafficking of the B cell receptor (BCR, shown in red) and presumably also its downstream signalling. Since SPPL2a is required for clearance of the CD74 NTF, activity of this protease indirectly has a major impact on signal transduction in B cells. c, d SPP/SPPL proteases can also directly be involved in proteolytic processing of active receptor proteins like the Lectin-like oxidised low-density lipoprotein receptor 1 (LOX-1). In this case, the receptor NTFs can act as enhancers of the signaling of the full length receptor, which is induced by oxidised LDL (oxLDL) (c). Thus, turnover of the NTF controls LOX-1 signalling. Furthermore, the LOX-1 NTF was found to be an active signalling protein itself (d). In an autonomous way, most likely without the need of a ligand, this fragment activates MAP kinases. Therefore, the cellular levels of this fragment—controlled by SPP/SPPL proteases—are a direct determinant of the resulting signalling activation

Fig. 3

The role of SPPL2c in the murine testis. SPPL2c shows selective expression in elongated spermatids. In these cells, SPPL2c resides in the endoplasmic reticulum (ER). Two in vivo substrates of this protease have been identified: the SNARE protein syntaxin 8 (Stx8) and Phospholamban (PLN), an interactor and inhibitor of the SERCA Ca²⁺ ATPase. Both proteins accumulate in the testis of SPPL2c-deficient mice. As functional consequences of SPPL2c-deficiency, handling of Ca²⁺ and membrane trafficking in the secretory pathway are altered in spermatids. SPPL2c^−/− spermatids show a reduced cytoplasmic Ca²⁺ concentration. Furthermore, the organisation of the Golgi apparatus is less compact which may have implications for the protein delivery to the forming acrosome. Mature SPPL2c^−/− sperm cells show an altered glycosylation pattern presumably reflecting alterations of glycosyltransferase trafficking which has been characterised in SPPL2c-overexpressing HEK cells

Fig. 4

Pathophysiological functions of SPP/SPPL proteases. Summary of the proteases’ in vivo functions based on phenotypes of the respective protease-deficient mouse models. For each pathophysiological process, the implicated protease and the responsible substrate (if known) are listed