Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors
Abstract Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. E...
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BMC
2025-04-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02208-w |
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| author | Michaela Bosakova Sara P. Abraham Davis Wachtell Jennifer T. Zieba Alexander Kot Alexandru Nita Aleksandra Anna Czyrek Adolf Koudelka Vlad-Constantin Ursachi Zuzana Feketova Gustavo Rico-Llanos Katerina Svozilova Petra Kocerova Bohumil Fafilek Tomas Gregor Jana Kotaskova Ivan Duran Petr Vanhara Michael Doubek Jiri Mayer Karel Soucek Deborah Krakow Pavel Krejci |
| author_facet | Michaela Bosakova Sara P. Abraham Davis Wachtell Jennifer T. Zieba Alexander Kot Alexandru Nita Aleksandra Anna Czyrek Adolf Koudelka Vlad-Constantin Ursachi Zuzana Feketova Gustavo Rico-Llanos Katerina Svozilova Petra Kocerova Bohumil Fafilek Tomas Gregor Jana Kotaskova Ivan Duran Petr Vanhara Michael Doubek Jiri Mayer Karel Soucek Deborah Krakow Pavel Krejci |
| author_sort | Michaela Bosakova |
| collection | DOAJ |
| description | Abstract Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment. |
| format | Article |
| id | doaj-art-a0c20813d187493c9ddcdcc2d7590dfd |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-a0c20813d187493c9ddcdcc2d7590dfd2025-08-20T02:15:28ZengBMCCell Communication and Signaling1478-811X2025-04-0123111710.1186/s12964-025-02208-wEndoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptorsMichaela Bosakova0Sara P. Abraham1Davis Wachtell2Jennifer T. Zieba3Alexander Kot4Alexandru Nita5Aleksandra Anna Czyrek6Adolf Koudelka7Vlad-Constantin Ursachi8Zuzana Feketova9Gustavo Rico-Llanos10Katerina Svozilova11Petra Kocerova12Bohumil Fafilek13Tomas Gregor14Jana Kotaskova15Ivan Duran16Petr Vanhara17Michael Doubek18Jiri Mayer19Karel Soucek20Deborah Krakow21Pavel Krejci22Department of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Orthopaedic Surgery, Human Genetics, and Obstetrics and Gynecology, University of California at Los AngelesDepartment of Orthopaedic Surgery, Human Genetics, and Obstetrics and Gynecology, University of California at Los AngelesDepartment of Orthopaedic Surgery, Human Genetics, and Obstetrics and Gynecology, University of California at Los AngelesDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Internal Medicine, Hematology and Oncology, University Hospital BrnoDepartment of Orthopaedic Surgery, Human Genetics, and Obstetrics and Gynecology, University of California at Los AngelesDepartment of Histology and Embryology, Faculty of Medicine, Masaryk UniversityDepartment of Internal Medicine, Hematology and Oncology, University Hospital BrnoDepartment of Internal Medicine, Hematology and Oncology, University Hospital BrnoInternational Clinical Research Center, St. Anne’s University HospitalDepartment of Orthopaedic Surgery, Human Genetics, and Obstetrics and Gynecology, University of California at Los AngelesDepartment of Biology, Faculty of Medicine, Masaryk UniversityAbstract Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.https://doi.org/10.1186/s12964-025-02208-wEndoplasmic reticulumERStressReceptorTransmembraneSignaling |
| spellingShingle | Michaela Bosakova Sara P. Abraham Davis Wachtell Jennifer T. Zieba Alexander Kot Alexandru Nita Aleksandra Anna Czyrek Adolf Koudelka Vlad-Constantin Ursachi Zuzana Feketova Gustavo Rico-Llanos Katerina Svozilova Petra Kocerova Bohumil Fafilek Tomas Gregor Jana Kotaskova Ivan Duran Petr Vanhara Michael Doubek Jiri Mayer Karel Soucek Deborah Krakow Pavel Krejci Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors Cell Communication and Signaling Endoplasmic reticulum ER Stress Receptor Transmembrane Signaling |
| title | Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| title_full | Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| title_fullStr | Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| title_full_unstemmed | Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| title_short | Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| title_sort | endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors |
| topic | Endoplasmic reticulum ER Stress Receptor Transmembrane Signaling |
| url | https://doi.org/10.1186/s12964-025-02208-w |
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