Institute for Physiological Chemistry, Technische Universität Dresden, Fiedlerstraße 42, D-01307 Dresden, Germany.
Institute for Physiological Chemistry, Technische Universität Dresden, Fiedlerstraße 42, D-01307 Dresden, Germany.
Biochim Biophys Acta Mol Cell Res. 2022 Jan;1869(1):119163. doi: 10.1016/j.bbamcr.2021.119163. Epub 2021 Oct 18.
Signal peptide peptidase-like 2 (SPPL) proteases constitute a subfamily of SPP/SPPL intramembrane proteases which are homologues of the presenilins, the catalytic core of the γ-secretase complex. The three SPPL2 proteases SPPL2a, SPPL2b and SPPL2c proteolyse single-span, type II-oriented transmembrane proteins and/or tail-anchored proteins within their hydrophobic transmembrane segments. We review recent progress in defining substrate spectra and in vivo functions of these proteases. Characterisation of the respective knockout mice has implicated SPPL2 proteases in immune cell differentiation and function, prevention of atherosclerotic plaque development and spermatogenesis. Mechanisms how substrates are selected by these enzymes are still incompletely understood. We will discuss current views on how selective SPPL2-mediated cleavage is or whether these proteases may exhibit a generalised role in the turnover of membrane proteins. This has been suggested previously for the mechanistically related γ-secretase for which the term "proteasome of the membrane" has been coined based on its broad substrate spectrum. With regard to individual substrates, potential signalling functions of the resulting cytosolic cleavage fragments remain a controversial aspect. However, it has been clearly shown that SPPL2 proteases can influence cellular signalling and membrane trafficking by controlling levels of their membrane-bound substrate proteins which highlights these enzymes as regulatory switches. Based on this, regulatory mechanisms controlling activity of SPPL2 proteases would need to be postulated, which are just beginning to emerge. These different questions, which are relevant for other families of intramembrane proteases in a similar way, will be critically discussed based on the current state of knowledge.
信号肽肽酶样 2 (SPPL) 蛋白酶构成 SPP/SPPL 跨膜蛋白酶亚家族，是 γ-分泌酶复合物的催化核心早老素的同源物。三种 SPPL2 蛋白酶 SPPL2a、SPPL2b 和 SPPL2c 在其疏水性跨膜区域内切割单跨、面向 II 型的跨膜蛋白和/或尾部锚定蛋白。我们回顾了最近在定义这些蛋白酶的底物谱和体内功能方面的进展。对各自敲除小鼠的特征分析表明，SPPL2 蛋白酶参与免疫细胞分化和功能、动脉粥样硬化斑块形成的预防和精子发生。这些酶如何选择底物的机制仍不完全清楚。我们将讨论目前关于 SPPL2 介导的切割是否具有选择性的观点，或者这些蛋白酶是否可能在膜蛋白的周转中发挥一般性作用。这一点先前已经被机制上相关的 γ-分泌酶提出，基于其广泛的底物谱，该酶被称为“膜的蛋白酶体”。就个别底物而言，由此产生的胞质切割片段的潜在信号功能仍然是一个有争议的方面。然而，已经清楚地表明，SPPL2 蛋白酶可以通过控制其膜结合底物蛋白的水平来影响细胞信号和膜运输，这突出了这些酶作为调节开关的作用。基于此，可以推测控制 SPPL2 蛋白酶活性的调节机制，这些机制才刚刚开始出现。这些不同的问题对于其他跨膜蛋白酶家族也具有类似的重要性，将根据当前的知识状况进行批判性讨论。
