ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response
The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is uncl...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227522001122 |
| _version_ | 1828141936727293952 |
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| author | Asli D. Yildirim Mevlut Citir Asli E. Dogan Zehra Veli Zehra Yildirim Ozlem Tufanli Alexis Traynor-Kaplan Carsten Schultz Ebru Erbay |
| author_facet | Asli D. Yildirim Mevlut Citir Asli E. Dogan Zehra Veli Zehra Yildirim Ozlem Tufanli Alexis Traynor-Kaplan Carsten Schultz Ebru Erbay |
| author_sort | Asli D. Yildirim |
| collection | DOAJ |
| description | The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells. |
| first_indexed | 2024-04-11T19:33:11Z |
| format | Article |
| id | doaj.art-978a54790e714435803d399ad90aff41 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-11T19:33:11Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-978a54790e714435803d399ad90aff412022-12-22T04:06:56ZengElsevierJournal of Lipid Research0022-22752022-10-016310100279ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein ResponseAsli D. Yildirim0Mevlut Citir1Asli E. Dogan2Zehra Veli3Zehra Yildirim4Ozlem Tufanli5Alexis Traynor-Kaplan6Carsten Schultz7Ebru Erbay8Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, TurkeyCell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, GermanySmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, TurkeyNational Nanotechnology Center, Bilkent University, Ankara, TurkeySmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, TurkeyNew York University, Langone Medical Center, New York, NY, USADepartment of Medicine, Washington University School of Medicine, Seattle, USA; ATK Innovation, Analytics and Discovery, North Bend, WA, USADepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, USASmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine, University of California, Los Angeles, CA, USA; For correspondence: Ebru ErbayThe unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells.http://www.sciencedirect.com/science/article/pii/S0022227522001122adaptive stress responseendoplasmic reticulummitochondriainositol-requiring enzyme-1endoribonucleasekinase |
| spellingShingle | Asli D. Yildirim Mevlut Citir Asli E. Dogan Zehra Veli Zehra Yildirim Ozlem Tufanli Alexis Traynor-Kaplan Carsten Schultz Ebru Erbay ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response Journal of Lipid Research adaptive stress response endoplasmic reticulum mitochondria inositol-requiring enzyme-1 endoribonuclease kinase |
| title | ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response |
| title_full | ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response |
| title_fullStr | ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response |
| title_full_unstemmed | ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response |
| title_short | ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response |
| title_sort | er stress induced sphingosine 1 phosphate lyase phosphorylation potentiates the mitochondrial unfolded protein response |
| topic | adaptive stress response endoplasmic reticulum mitochondria inositol-requiring enzyme-1 endoribonuclease kinase |
| url | http://www.sciencedirect.com/science/article/pii/S0022227522001122 |
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