Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP
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 homo...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-01-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216491 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849226053295276032 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Luke A Perera |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-39116a8baac7473c85e71501c8fe0c4e |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-39116a8baac7473c85e71501c8fe0c4e2025-08-24T11:43:18ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-01-0115311610.15252/emmm.202216491Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiPLuke A Perera0Andrew T Hattersley1Heather P Harding2Matthew N Wakeling3Sarah E Flanagan4Ibrahim Mohsina5Jamal Raza6Alice Gardham7David Ron8Elisa De Franco9Cambridge Institute for Medical Research, University of CambridgeInstitute of Biomedical and Clinical Science, College of Medicine and Health, University of ExeterCambridge Institute for Medical Research, University of CambridgeInstitute of Biomedical and Clinical Science, College of Medicine and Health, University of ExeterInstitute of Biomedical and Clinical Science, College of Medicine and Health, University of ExeterDepartment of Endocrine and Diabetes, National Institute of Child HealthDepartment of Endocrine and Diabetes, National Institute of Child HealthNorth West Thames Regional Genetics ServiceCambridge Institute for Medical Research, University of CambridgeInstitute of Biomedical and Clinical Science, College of Medicine and Health, University of ExeterAbstract 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.https://doi.org/10.15252/emmm.202216491diabetes mellitusendoplasmic reticulum chaperonemutationnucleotidyltransferasespost‐translational |
| spellingShingle | 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 Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP EMBO Molecular Medicine diabetes mellitus endoplasmic reticulum chaperone mutation nucleotidyltransferases post‐translational |
| title | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
| title_full | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
| title_fullStr | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
| title_full_unstemmed | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
| title_short | Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP |
| title_sort | infancy onset diabetes caused by de regulated ampylation of the human endoplasmic reticulum chaperone bip |
| topic | diabetes mellitus endoplasmic reticulum chaperone mutation nucleotidyltransferases post‐translational |
| url | https://doi.org/10.15252/emmm.202216491 |
| work_keys_str_mv | AT lukeaperera infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT andrewthattersley infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT heatherpharding infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT matthewnwakeling infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT saraheflanagan infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT ibrahimmohsina infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT jamalraza infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT alicegardham infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT davidron infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip AT elisadefranco infancyonsetdiabetescausedbyderegulatedampylationofthehumanendoplasmicreticulumchaperonebip |