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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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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. |
format | Online Article Text |
id | pubmed-4068138 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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