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An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis
Nearly one‐third of nascent proteins are initially targeted to the endoplasmic reticulum (ER), where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER‐associated degradation (ERAD) remov...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929635/ https://www.ncbi.nlm.nih.gov/pubmed/36350249 http://dx.doi.org/10.15252/embj.2022112275 |
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author | Bhaduri, Satarupa Aguayo, Analine Ohno, Yusuke Proietto, Marco Jung, Jasmine Wang, Isabel Kandel, Rachel Singh, Narinderbir Ibrahim, Ikran Fulzele, Amit Bennett, Eric J Kihara, Akio Neal, Sonya E |
author_facet | Bhaduri, Satarupa Aguayo, Analine Ohno, Yusuke Proietto, Marco Jung, Jasmine Wang, Isabel Kandel, Rachel Singh, Narinderbir Ibrahim, Ikran Fulzele, Amit Bennett, Eric J Kihara, Akio Neal, Sonya E |
author_sort | Bhaduri, Satarupa |
collection | PubMed |
description | Nearly one‐third of nascent proteins are initially targeted to the endoplasmic reticulum (ER), where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER‐associated degradation (ERAD) removes these client proteins from the ER membrane to the cytosol in a process known as retrotranslocation. Our previous work demonstrated that rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated membrane integral ERAD substrates. Herein, we found that Dfm1 associates with the SPOTS complex, which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components that are critical for catalyzing the first rate‐limiting step of the sphingolipid biosynthesis pathway. Furthermore, Dfm1 employs an ERAD‐independent role for facilitating the ER export and endosome‐ and Golgi‐associated degradation (EGAD) of Orm2, which is a major antagonist of SPT activity. Given that the accumulation of human Orm2 homologs, ORMDLs, is associated with various pathologies, our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases. |
format | Online Article Text |
id | pubmed-9929635 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99296352023-02-16 An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis Bhaduri, Satarupa Aguayo, Analine Ohno, Yusuke Proietto, Marco Jung, Jasmine Wang, Isabel Kandel, Rachel Singh, Narinderbir Ibrahim, Ikran Fulzele, Amit Bennett, Eric J Kihara, Akio Neal, Sonya E EMBO J Articles Nearly one‐third of nascent proteins are initially targeted to the endoplasmic reticulum (ER), where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER‐associated degradation (ERAD) removes these client proteins from the ER membrane to the cytosol in a process known as retrotranslocation. Our previous work demonstrated that rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated membrane integral ERAD substrates. Herein, we found that Dfm1 associates with the SPOTS complex, which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components that are critical for catalyzing the first rate‐limiting step of the sphingolipid biosynthesis pathway. Furthermore, Dfm1 employs an ERAD‐independent role for facilitating the ER export and endosome‐ and Golgi‐associated degradation (EGAD) of Orm2, which is a major antagonist of SPT activity. Given that the accumulation of human Orm2 homologs, ORMDLs, is associated with various pathologies, our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases. John Wiley and Sons Inc. 2022-11-09 /pmc/articles/PMC9929635/ /pubmed/36350249 http://dx.doi.org/10.15252/embj.2022112275 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Bhaduri, Satarupa Aguayo, Analine Ohno, Yusuke Proietto, Marco Jung, Jasmine Wang, Isabel Kandel, Rachel Singh, Narinderbir Ibrahim, Ikran Fulzele, Amit Bennett, Eric J Kihara, Akio Neal, Sonya E An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title | An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title_full | An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title_fullStr | An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title_full_unstemmed | An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title_short | An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis |
title_sort | erad‐independent role for rhomboid pseudoprotease dfm1 in mediating sphingolipid homeostasis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929635/ https://www.ncbi.nlm.nih.gov/pubmed/36350249 http://dx.doi.org/10.15252/embj.2022112275 |
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