Cargando…
Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex
The initial folding of secreted proteins occurs in the ER lumen, which contains specific chaperones and where posttranslational modifications may occur. Therefore lack of translocation, regardless of entry route or protein identity, is a highly toxic event, as the newly synthesized polypeptide is mi...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626058/ https://www.ncbi.nlm.nih.gov/pubmed/26337389 http://dx.doi.org/10.1091/mbc.E15-02-0085 |
_version_ | 1782398067824132096 |
---|---|
author | Braunstein, Ilana Zach, Lolita Allan, Susanne Kalies, Kai-Uwe Stanhill, Ariel |
author_facet | Braunstein, Ilana Zach, Lolita Allan, Susanne Kalies, Kai-Uwe Stanhill, Ariel |
author_sort | Braunstein, Ilana |
collection | PubMed |
description | The initial folding of secreted proteins occurs in the ER lumen, which contains specific chaperones and where posttranslational modifications may occur. Therefore lack of translocation, regardless of entry route or protein identity, is a highly toxic event, as the newly synthesized polypeptide is misfolded and can promiscuously interact with cytosolic factors. Mislocalized proteins bearing a signal sequence that did not successfully translocate through the translocon complex are subjected to a preemptive quality control (pQC) pathway and are degraded by the ubiquitin-proteasome system (UPS). In contrast to UPS-mediated, ER-associated degradation, few components involved in pQC have been identified. Here we demonstrate that on specific translocation inhibition, a p97–AIRAPL complex directly binds and regulates the efficient processing of polyubiquitinated pQC substrates by the UPS. We also demonstrate p97’s role in pQC processing of preproinsulin in cases of naturally occurring mutations within the signal sequence of insulin. |
format | Online Article Text |
id | pubmed-4626058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-46260582016-01-16 Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex Braunstein, Ilana Zach, Lolita Allan, Susanne Kalies, Kai-Uwe Stanhill, Ariel Mol Biol Cell Articles The initial folding of secreted proteins occurs in the ER lumen, which contains specific chaperones and where posttranslational modifications may occur. Therefore lack of translocation, regardless of entry route or protein identity, is a highly toxic event, as the newly synthesized polypeptide is misfolded and can promiscuously interact with cytosolic factors. Mislocalized proteins bearing a signal sequence that did not successfully translocate through the translocon complex are subjected to a preemptive quality control (pQC) pathway and are degraded by the ubiquitin-proteasome system (UPS). In contrast to UPS-mediated, ER-associated degradation, few components involved in pQC have been identified. Here we demonstrate that on specific translocation inhibition, a p97–AIRAPL complex directly binds and regulates the efficient processing of polyubiquitinated pQC substrates by the UPS. We also demonstrate p97’s role in pQC processing of preproinsulin in cases of naturally occurring mutations within the signal sequence of insulin. The American Society for Cell Biology 2015-11-01 /pmc/articles/PMC4626058/ /pubmed/26337389 http://dx.doi.org/10.1091/mbc.E15-02-0085 Text en © 2015 Braunstein et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Braunstein, Ilana Zach, Lolita Allan, Susanne Kalies, Kai-Uwe Stanhill, Ariel Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title | Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title_full | Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title_fullStr | Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title_full_unstemmed | Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title_short | Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex |
title_sort | proteasomal degradation of preemptive quality control (pqc) substrates is mediated by an airapl–p97 complex |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626058/ https://www.ncbi.nlm.nih.gov/pubmed/26337389 http://dx.doi.org/10.1091/mbc.E15-02-0085 |
work_keys_str_mv | AT braunsteinilana proteasomaldegradationofpreemptivequalitycontrolpqcsubstratesismediatedbyanairaplp97complex AT zachlolita proteasomaldegradationofpreemptivequalitycontrolpqcsubstratesismediatedbyanairaplp97complex AT allansusanne proteasomaldegradationofpreemptivequalitycontrolpqcsubstratesismediatedbyanairaplp97complex AT kalieskaiuwe proteasomaldegradationofpreemptivequalitycontrolpqcsubstratesismediatedbyanairaplp97complex AT stanhillariel proteasomaldegradationofpreemptivequalitycontrolpqcsubstratesismediatedbyanairaplp97complex |