Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression
Abstract Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA‐binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is kno...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202115344 |
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| author | Zehra Yildirim Sabyasachi Baboo Syed M Hamid Asli E Dogan Ozlem Tufanli Sabrina Robichaud Christina Emerton Jolene K Diedrich Hasan Vatandaslar Fotis Nikolos Yanghong Gu Takao Iwawaki Elizabeth Tarling Mireille Ouimet David L Nelson John R Yates Peter Walter Ebru Erbay |
| author_facet | Zehra Yildirim Sabyasachi Baboo Syed M Hamid Asli E Dogan Ozlem Tufanli Sabrina Robichaud Christina Emerton Jolene K Diedrich Hasan Vatandaslar Fotis Nikolos Yanghong Gu Takao Iwawaki Elizabeth Tarling Mireille Ouimet David L Nelson John R Yates Peter Walter Ebru Erbay |
| author_sort | Zehra Yildirim |
| collection | DOAJ |
| description | Abstract Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA‐binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP‐bound mRNAs. We show ER stress‐induced activation of Inositol requiring enzyme‐1 (IRE1), an ER‐resident stress‐sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress‐induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis. |
| format | Article |
| id | doaj-art-b76dfacbb1c646c7852f08635a49b842 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b76dfacbb1c646c7852f08635a49b8422025-08-20T03:43:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-02-0114412210.15252/emmm.202115344Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progressionZehra Yildirim0Sabyasachi Baboo1Syed M Hamid2Asli E Dogan3Ozlem Tufanli4Sabrina Robichaud5Christina Emerton6Jolene K Diedrich7Hasan Vatandaslar8Fotis Nikolos9Yanghong Gu10Takao Iwawaki11Elizabeth Tarling12Mireille Ouimet13David L Nelson14John R Yates15Peter Walter16Ebru Erbay17Department of Cardiology, Smidt Heart Institute, Cedars‐Sinai Medical CenterDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Cardiology, Smidt Heart Institute, Cedars‐Sinai Medical CenterDepartment of Cardiology, Smidt Heart Institute, Cedars‐Sinai Medical CenterLagone Medical Center, New York UniversityDepartment of Biochemistry, Microbiology and Immunology, Heart Institute, University of OttawaDepartment of Biochemistry, Microbiology and Immunology, Heart Institute, University of OttawaDepartment of Molecular Medicine, The Scripps Research InstituteInstitute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH)Samuel Oschin Cancer Center, Cedars‐Sinai Medical CenterDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Life Science, Medical Research Institute, Kanazawa Medical UniversityDepartment of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San FranciscoDepartment of Biochemistry, Microbiology and Immunology, Heart Institute, University of OttawaDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San FranciscoDepartment of Cardiology, Smidt Heart Institute, Cedars‐Sinai Medical CenterAbstract Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA‐binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP‐bound mRNAs. We show ER stress‐induced activation of Inositol requiring enzyme‐1 (IRE1), an ER‐resident stress‐sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress‐induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.https://doi.org/10.15252/emmm.202115344atherosclerosischolesterol homeostasisefferocytosisER stresstranslational regulation |
| spellingShingle | Zehra Yildirim Sabyasachi Baboo Syed M Hamid Asli E Dogan Ozlem Tufanli Sabrina Robichaud Christina Emerton Jolene K Diedrich Hasan Vatandaslar Fotis Nikolos Yanghong Gu Takao Iwawaki Elizabeth Tarling Mireille Ouimet David L Nelson John R Yates Peter Walter Ebru Erbay Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression EMBO Molecular Medicine atherosclerosis cholesterol homeostasis efferocytosis ER stress translational regulation |
| title | Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression |
| title_full | Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression |
| title_fullStr | Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression |
| title_full_unstemmed | Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression |
| title_short | Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression |
| title_sort | intercepting ire1 kinase fmrp signaling prevents atherosclerosis progression |
| topic | atherosclerosis cholesterol homeostasis efferocytosis ER stress translational regulation |
| url | https://doi.org/10.15252/emmm.202115344 |
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