دورية أكاديمية
Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP
| العنوان: | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
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| المؤلفون: | Luke A Perera, Andrew T Hattersley, Heather P Harding, Matthew N Wakeling, Sarah E Flanagan, Ibrahim Mohsina, Jamal Raza, Alice Gardham, David Ron, Elisa De Franco |
| المصدر: | EMBO Molecular Medicine, Vol 15, Iss 3, Pp n/a-n/a (2023) |
| بيانات النشر: | Springer Nature, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Medicine (General) LCC:Genetics |
| مصطلحات موضوعية: | diabetes mellitus, endoplasmic reticulum chaperone, mutation, nucleotidyltransferases, post‐translational, Medicine (General), R5-920, Genetics, QH426-470 |
| الوصف: | Abstract Dysfunction of the endoplasmic reticulum (ER) in insulin‐producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy‐onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain‐containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock‐in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de‐regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1757-4684 1757-4676 20221649 |
| العلاقة: | https://doaj.org/toc/1757-4676Test; https://doaj.org/toc/1757-4684Test |
| DOI: | 10.15252/emmm.202216491 |
| الوصول الحر: | https://doaj.org/article/39116a8baac7473c85e71501c8fe0c4eTest |
| رقم الانضمام: | edsdoj.39116a8baac7473c85e71501c8fe0c4e |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17574684 17574676 20221649 |
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| DOI: | 10.15252/emmm.202216491 |