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Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins

The regulated turnover of endoplasmic reticulum (ER)–resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but ha...

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Autores principales: Boname, Jessica M., Bloor, Stuart, Wandel, Michal P., Nathan, James A., Antrobus, Robin, Dingwell, Kevin S., Thurston, Teresa L., Smith, Duncan L., Smith, James C., Randow, Felix, Lehner, Paul J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068138/
https://www.ncbi.nlm.nih.gov/pubmed/24958774
http://dx.doi.org/10.1083/jcb.201312009
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author Boname, Jessica M.
Bloor, Stuart
Wandel, Michal P.
Nathan, James A.
Antrobus, Robin
Dingwell, Kevin S.
Thurston, Teresa L.
Smith, Duncan L.
Smith, James C.
Randow, Felix
Lehner, Paul J.
author_facet Boname, Jessica M.
Bloor, Stuart
Wandel, Michal P.
Nathan, James A.
Antrobus, Robin
Dingwell, Kevin S.
Thurston, Teresa L.
Smith, Duncan L.
Smith, James C.
Randow, Felix
Lehner, Paul J.
author_sort Boname, Jessica M.
collection PubMed
description The regulated turnover of endoplasmic reticulum (ER)–resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but has never been shown for endogenous substrates. To determine whether intramembrane proteolysis, specifically cleavage by the intramembrane-cleaving aspartyl protease signal peptide peptidase (SPP), is involved in this pathway, we generated an SPP-specific somatic cell knockout. In a stable isotope labeling by amino acids in cell culture–based proteomics screen, we identified HO-1 (heme oxygenase-1), the rate-limiting enzyme in the degradation of heme to biliverdin, as a novel SPP substrate. Intramembrane cleavage by catalytically active SPP provided the primary proteolytic step required for the extraction and subsequent proteasome-dependent degradation of HO-1, an ER-resident tail-anchored protein. SPP-mediated proteolysis was not limited to HO-1 but was required for the dislocation and degradation of additional tail-anchored ER-resident proteins. Our study identifies tail-anchored proteins as novel SPP substrates and a specific requirement for SPP-mediated intramembrane cleavage in protein turnover.
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spelling pubmed-40681382014-12-23 Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins Boname, Jessica M. Bloor, Stuart Wandel, Michal P. Nathan, James A. Antrobus, Robin Dingwell, Kevin S. Thurston, Teresa L. Smith, Duncan L. Smith, James C. Randow, Felix Lehner, Paul J. J Cell Biol Research Articles The regulated turnover of endoplasmic reticulum (ER)–resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but has never been shown for endogenous substrates. To determine whether intramembrane proteolysis, specifically cleavage by the intramembrane-cleaving aspartyl protease signal peptide peptidase (SPP), is involved in this pathway, we generated an SPP-specific somatic cell knockout. In a stable isotope labeling by amino acids in cell culture–based proteomics screen, we identified HO-1 (heme oxygenase-1), the rate-limiting enzyme in the degradation of heme to biliverdin, as a novel SPP substrate. Intramembrane cleavage by catalytically active SPP provided the primary proteolytic step required for the extraction and subsequent proteasome-dependent degradation of HO-1, an ER-resident tail-anchored protein. SPP-mediated proteolysis was not limited to HO-1 but was required for the dislocation and degradation of additional tail-anchored ER-resident proteins. Our study identifies tail-anchored proteins as novel SPP substrates and a specific requirement for SPP-mediated intramembrane cleavage in protein turnover. The Rockefeller University Press 2014-06-23 /pmc/articles/PMC4068138/ /pubmed/24958774 http://dx.doi.org/10.1083/jcb.201312009 Text en © 2014 Boname et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Boname, Jessica M.
Bloor, Stuart
Wandel, Michal P.
Nathan, James A.
Antrobus, Robin
Dingwell, Kevin S.
Thurston, Teresa L.
Smith, Duncan L.
Smith, James C.
Randow, Felix
Lehner, Paul J.
Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title_full Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title_fullStr Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title_full_unstemmed Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title_short Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
title_sort cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068138/
https://www.ncbi.nlm.nih.gov/pubmed/24958774
http://dx.doi.org/10.1083/jcb.201312009
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