Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis
The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000274 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850216906717396992 |
|---|---|
| author | Amanda K. Casey Nathan M. Stewart Naqi Zaidi Hillery F. Gray Hazel A. Fields Masahiro Sakurai Carlos A. Pinzon-Arteaga Bret M. Evers Jun Wu Kim Orth |
| author_facet | Amanda K. Casey Nathan M. Stewart Naqi Zaidi Hillery F. Gray Hazel A. Fields Masahiro Sakurai Carlos A. Pinzon-Arteaga Bret M. Evers Jun Wu Kim Orth |
| author_sort | Amanda K. Casey |
| collection | DOAJ |
| description | The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicDR371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicDR371S mice appeared normal at birth, adult mFicDR371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicDR371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience. |
| format | Article |
| id | doaj-art-c1f0c53ca2f1446aafeff598ee9c5812 |
| institution | OA Journals |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-c1f0c53ca2f1446aafeff598ee9c58122025-08-20T02:08:11ZengElsevierMolecular Metabolism2212-87782025-05-019510212010.1016/j.molmet.2025.102120Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasisAmanda K. Casey0Nathan M. Stewart1Naqi Zaidi2Hillery F. Gray3Hazel A. Fields4Masahiro Sakurai5Carlos A. Pinzon-Arteaga6Bret M. Evers7Jun Wu8Kim Orth9Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USADepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Corresponding author. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicDR371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicDR371S mice appeared normal at birth, adult mFicDR371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicDR371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.http://www.sciencedirect.com/science/article/pii/S2212877825000274AMPylationBiPFicDInsulinIslet biologyNeonatal diabetes |
| spellingShingle | Amanda K. Casey Nathan M. Stewart Naqi Zaidi Hillery F. Gray Hazel A. Fields Masahiro Sakurai Carlos A. Pinzon-Arteaga Bret M. Evers Jun Wu Kim Orth Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis Molecular Metabolism AMPylation BiP FicD Insulin Islet biology Neonatal diabetes |
| title | Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| title_full | Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| title_fullStr | Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| title_full_unstemmed | Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| title_short | Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| title_sort | pre clinical model of dysregulated ficd ampylation causes diabetes by disrupting pancreatic endocrine homeostasis |
| topic | AMPylation BiP FicD Insulin Islet biology Neonatal diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000274 |
| work_keys_str_mv | AT amandakcasey preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT nathanmstewart preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT naqizaidi preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT hilleryfgray preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT hazelafields preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT masahirosakurai preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT carlosapinzonarteaga preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT bretmevers preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT junwu preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis AT kimorth preclinicalmodelofdysregulatedficdampylationcausesdiabetesbydisruptingpancreaticendocrinehomeostasis |