Institute for Physiological Chemistry, Technische Universität Dresden, Germany.
Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Germany.
FEBS J. 2024 Jan;291(1):25-44. doi: 10.1111/febs.16941. Epub 2023 Sep 5.
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.
信号肽肽酶 (SPP) 和四种 SPP 样蛋白酶 SPPL2a、SPPL2b、SPPL2c 和 SPPL3 构成了天冬氨酸跨膜蛋白酶家族，与早老素具有同源性。不同的成员位于分泌途径和内体溶酶体系统中的不同细胞定位。尽管具有不同的切割特性，但它们都切割具有 II 型取向的单跨跨膜蛋白，表现出胞质 N 末端。尽管底物的鉴定尚未完成，但 SPP/SPPL 介导的蛋白水解似乎具有相当的选择性。因此，根据我们目前的理解，SPP/SPPL 蛋白酶的切割似乎更多地起到调节作用，而不是作为批量蛋白水解途径。在本综述中，我们将总结我们对 SPP/SPPL 蛋白酶的了解，特别是强调最近鉴定的底物以及这些切割事件的功能和/或（病理）生理意义。在此基础上，我们旨在概述该领域当前存在的问题。这些问题与细胞水平上这些蛋白酶的调节有关，也与疾病和病理生理过程有关。此外，与能够降解膜蛋白的其他蛋白稳态系统的相互作用开始显现。
