Leinung Nadja, Mentrup Torben, Patel Mehul, Gallagher Tom, Schröder Bernd
Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA.
iScience. 2023 Sep 4;26(10):107819. doi: 10.1016/j.isci.2023.107819. eCollection 2023 Oct 20.
Signal peptide peptidase-like 2a and b (SPPL2a/b) are aspartyl intramembrane proteases and cleave tail-anchored proteins as well as N-terminal fragments (NTFs) derived from type II-oriented transmembrane proteins. How these proteases recruit substrates and cleavage is regulated, is still incompletely understood. We found that SPPL2a/b localize to detergent-resistant membrane (DRM) domains with the characteristics of tetraspanin-enriched microdomains (TEMs). Based on this, association with several tetraspanins was evaluated. We demonstrate that not only SPPL2a/b but also their substrates tumor necrosis factor (TNF) and CD74 associate with tetraspanins like CD9, CD81, and CD82 and/or TEMs and analyze the stability of these complexes in different detergents. CD9 and CD81 deficiency has protease- and substrate-selective effects on SPPL2a/b function. Our findings suggest that reciprocal interactions with tetraspanins may assist protease-substrate encounters of SPPL2a/b within the membrane. Beyond SPP/SPPL proteases, this supports previous concepts that tetraspanins facilitate membrane-embedded proteolytic processes.
信号肽酶样蛋白2a和b（SPPL2a/b）是天冬氨酰基跨膜蛋白酶，可切割尾锚定蛋白以及源自II型跨膜蛋白的N端片段（NTF）。这些蛋白酶如何招募底物以及切割过程如何受到调控，目前仍未完全了解。我们发现SPPL2a/b定位于具有富含四跨膜蛋白微结构域（TEM）特征的耐去污剂膜（DRM）结构域。基于此，我们评估了其与几种四跨膜蛋白的关联。我们证明，不仅SPPL2a/b，而且它们的底物肿瘤坏死因子（TNF）和CD74都与CD9、CD81和CD82等四跨膜蛋白和/或TEM相关联，并分析了这些复合物在不同去污剂中的稳定性。CD9和CD81缺陷对SPPL2a/b功能具有蛋白酶和底物选择性作用。我们的研究结果表明，与四跨膜蛋白的相互作用可能有助于SPPL2a/b在膜内的蛋白酶-底物相互作用。除了SPP/SPPL蛋白酶外，这支持了先前关于四跨膜蛋白促进膜内蛋白水解过程的概念。
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