The role of SPP / SPPL intramembrane proteases in membrane protein homeostasis
Torben Mentrupa, Nadja Leinunga, Mehul Patela, Regina Fluhrerb c d e, Bernd Schrödera✉
- aInstitute for Physiological Chemistry Technische Universität Dresden Germany
- bBiochemistry and Molecular Biology, Institute of Theoretical Medicine, Faculty of Medicine University of Augsburg Germany
- cCenter for Interdisciplinary Health Research University of Augsburg Germany
- dBiochemistry and Molecular Biology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Germany
- eUniversity of Augsburg, Center for Interdisciplinary Health Research, 86135 Augsburg, Germany
- ✉Corresponding author
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Abstract
Signal peptide peptidase (SPP) and the four SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 constitute a family of aspartyl intramembrane proteases with homology to presenilins. The different members reside in distinct cellular localisations within the secretory pathway and the endo-lysosomal system. Despite individual cleavage characteristics, they all cleave single-span transmembrane proteins with a type II orientation exhibiting a cytosolic N-terminus. Though the identification of substrates is not complete, SPP/SPPL-mediated proteolysis appears to be rather selective. Therefore, according to our current understanding cleavage by SPP/SPPL proteases rather seems to serve a regulatory function than being a bulk proteolytic pathway. In the present review, we will summarise our state of knowledge on SPP/SPPL proteases and in particular highlight recently identified substrates and the functional and/or (patho)-physiological implications of these cleavage events. Based on this, we aim to provide an overview of the current open questions in the field. These are connected to the regulation of these proteases at the cellular level but also in context of disease and patho-physiological processes. Furthermore, the interplay with other proteostatic systems capable of degrading membrane proteins is beginning to emerge.
TL;DRThe present review will summarise the state of knowledge on SPP/SPPL proteases and in particular highlight recently identified substrates and the functional and/or (patho)‐physiological implications of these cleavage events. (Semantic Scholar)