Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering
Endoplasmic reticulum (ER) function is dedicated to multiple essential processes in eukaryotes, including the processing of secretory proteins and the biogenesis of most membrane lipids. These roles implicate a heavy burden to the organelle, and it is thus prone to fluctuations in the homeostasis of...
| Main Authors: | , , , , , |
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| Format: | Journal Article |
| Language: | English |
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MDPI
2022
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| Online Access: | http://hdl.handle.net/20.500.11937/96046 |
| _version_ | 1848766082143223808 |
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| author | Bieniawski, Mark A. Stevens, Kofi L.P. Witham, Christopher M. Steuart, Robert F. L. Bankaitis, V.A. Mousley, Carl J. |
| author_facet | Bieniawski, Mark A. Stevens, Kofi L.P. Witham, Christopher M. Steuart, Robert F. L. Bankaitis, V.A. Mousley, Carl J. |
| author_sort | Bieniawski, Mark A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Endoplasmic reticulum (ER) function is dedicated to multiple essential processes in eukaryotes, including the processing of secretory proteins and the biogenesis of most membrane lipids. These roles implicate a heavy burden to the organelle, and it is thus prone to fluctuations in the homeostasis of molecules which govern these processes. The unfolded protein response (UPR) is a general ER stress response tasked with maintaining the ER for optimal function, mediated by the master activator Ire1. Ire1 is an ER transmembrane protein that initiates the UPR, forming characteristic oligomers in response to irregularities in luminal protein folding and in the membrane lipid environment. The role of lipids in regulating the UPR remains relatively obscure; however, recent research has revealed a potent role for sphingolipids in its activity. Here, we identify a major role for the oxysterol-binding protein Kes1, whose activity is of consequence to the sphingolipid profile in cells resulting in an inhibition of UPR activity. Using an mCherry-tagged derivative of Ire1, we observe that this occurs due to inhibition of Ire1 to form oligomers. Furthermore, we identify that a sphingolipid presence is required for Ire1 activity, and that specific sphingolipid profiles are of major consequence to Ire1 function. In addition, we highlight cases where Ire1 oligomerization is absent despite an active UPR, revealing a potential mechanism for UPR induction where Ire1 oligomerization is not necessary. This work provides a basis for the role of sphingolipids in controlling the UPR, where their metabolism harbors a crucial role in regulating its onset. |
| first_indexed | 2025-11-14T11:45:29Z |
| format | Journal Article |
| id | curtin-20.500.11937-96046 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:45:29Z |
| publishDate | 2022 |
| publisher | MDPI |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-960462024-12-05T01:14:05Z Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering Bieniawski, Mark A. Stevens, Kofi L.P. Witham, Christopher M. Steuart, Robert F. L. Bankaitis, V.A. Mousley, Carl J. Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Multidisciplinary Chemistry unfolded protein response (UPR) Ire1 sphingolipids Kes1 Osh4 UNFOLDED PROTEIN RESPONSE STRESS SENSOR IRE1 SACCHAROMYCES METABOLISM ACTIVATION CERAMIDES MECHANISM STRAINS SIGNALS BINDING Ire1 Kes1 Osh4 sphingolipids unfolded protein response (UPR) Protein Serine-Threonine Kinases Sphingolipids Unfolded Protein Response Endoplasmic Reticulum Stress Cluster Analysis Oxysterols Endoribonucleases Endoribonucleases Sphingolipids Cluster Analysis Unfolded Protein Response Endoplasmic Reticulum Stress Oxysterols Protein Serine-Threonine Kinases Endoplasmic reticulum (ER) function is dedicated to multiple essential processes in eukaryotes, including the processing of secretory proteins and the biogenesis of most membrane lipids. These roles implicate a heavy burden to the organelle, and it is thus prone to fluctuations in the homeostasis of molecules which govern these processes. The unfolded protein response (UPR) is a general ER stress response tasked with maintaining the ER for optimal function, mediated by the master activator Ire1. Ire1 is an ER transmembrane protein that initiates the UPR, forming characteristic oligomers in response to irregularities in luminal protein folding and in the membrane lipid environment. The role of lipids in regulating the UPR remains relatively obscure; however, recent research has revealed a potent role for sphingolipids in its activity. Here, we identify a major role for the oxysterol-binding protein Kes1, whose activity is of consequence to the sphingolipid profile in cells resulting in an inhibition of UPR activity. Using an mCherry-tagged derivative of Ire1, we observe that this occurs due to inhibition of Ire1 to form oligomers. Furthermore, we identify that a sphingolipid presence is required for Ire1 activity, and that specific sphingolipid profiles are of major consequence to Ire1 function. In addition, we highlight cases where Ire1 oligomerization is absent despite an active UPR, revealing a potential mechanism for UPR induction where Ire1 oligomerization is not necessary. This work provides a basis for the role of sphingolipids in controlling the UPR, where their metabolism harbors a crucial role in regulating its onset. 2022 Journal Article http://hdl.handle.net/20.500.11937/96046 10.3390/ijms232012130 English http://creativecommons.org/licenses/by/4.0/ MDPI fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Multidisciplinary Chemistry unfolded protein response (UPR) Ire1 sphingolipids Kes1 Osh4 UNFOLDED PROTEIN RESPONSE STRESS SENSOR IRE1 SACCHAROMYCES METABOLISM ACTIVATION CERAMIDES MECHANISM STRAINS SIGNALS BINDING Ire1 Kes1 Osh4 sphingolipids unfolded protein response (UPR) Protein Serine-Threonine Kinases Sphingolipids Unfolded Protein Response Endoplasmic Reticulum Stress Cluster Analysis Oxysterols Endoribonucleases Endoribonucleases Sphingolipids Cluster Analysis Unfolded Protein Response Endoplasmic Reticulum Stress Oxysterols Protein Serine-Threonine Kinases Bieniawski, Mark A. Stevens, Kofi L.P. Witham, Christopher M. Steuart, Robert F. L. Bankaitis, V.A. Mousley, Carl J. Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title | Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title_full | Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title_fullStr | Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title_full_unstemmed | Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title_short | Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering |
| title_sort | diverse sphingolipid species harbor different effects on ire1 clustering |
| topic | Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Multidisciplinary Chemistry unfolded protein response (UPR) Ire1 sphingolipids Kes1 Osh4 UNFOLDED PROTEIN RESPONSE STRESS SENSOR IRE1 SACCHAROMYCES METABOLISM ACTIVATION CERAMIDES MECHANISM STRAINS SIGNALS BINDING Ire1 Kes1 Osh4 sphingolipids unfolded protein response (UPR) Protein Serine-Threonine Kinases Sphingolipids Unfolded Protein Response Endoplasmic Reticulum Stress Cluster Analysis Oxysterols Endoribonucleases Endoribonucleases Sphingolipids Cluster Analysis Unfolded Protein Response Endoplasmic Reticulum Stress Oxysterols Protein Serine-Threonine Kinases |
| url | http://hdl.handle.net/20.500.11937/96046 |