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Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains

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 incompletel...

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Autores principales: Leinung, Nadja, Mentrup, Torben, Patel, Mehul, Gallagher, Tom, Schröder, Bernd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509304/
https://www.ncbi.nlm.nih.gov/pubmed/37736044
http://dx.doi.org/10.1016/j.isci.2023.107819
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author Leinung, Nadja
Mentrup, Torben
Patel, Mehul
Gallagher, Tom
Schröder, Bernd
author_facet Leinung, Nadja
Mentrup, Torben
Patel, Mehul
Gallagher, Tom
Schröder, Bernd
author_sort Leinung, Nadja
collection PubMed
description 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.
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spelling pubmed-105093042023-09-21 Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains Leinung, Nadja Mentrup, Torben Patel, Mehul Gallagher, Tom Schröder, Bernd iScience Article 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. Elsevier 2023-09-04 /pmc/articles/PMC10509304/ /pubmed/37736044 http://dx.doi.org/10.1016/j.isci.2023.107819 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Leinung, Nadja
Mentrup, Torben
Patel, Mehul
Gallagher, Tom
Schröder, Bernd
Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title_full Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title_fullStr Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title_full_unstemmed Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title_short Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains
title_sort dynamic association of the intramembrane proteases sppl2a/b and their substrates with tetraspanin-enriched microdomains
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509304/
https://www.ncbi.nlm.nih.gov/pubmed/37736044
http://dx.doi.org/10.1016/j.isci.2023.107819
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