Journal
EMBO MOLECULAR MEDICINE
Volume 15, Issue 3, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202216491
Keywords
diabetes mellitus; endoplasmic reticulum chaperone; mutation; nucleotidyltransferases; post-translational
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Mutation in the FICD gene leads to dysfunction of the endoplasmic reticulum, resulting in cell loss and diabetes mellitus. The study suggests that regulating the activity of FICD may provide therapeutic benefits for treating related diseases.
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.
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