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Fic-mediated deAMPylation is not dependent on homodimerization and rescues toxic AMPylation in flies.


ABSTRACT: Protein chaperones play a critical role in proteostasis. The activity of the major endoplasmic reticulum chaperone BiP (GRP78) is regulated by Fic-mediated AMPylation during resting states. By contrast, during times of stress, BiP is deAMPylated. Here, we show that excessive AMPylation by a constitutively active FicE247G mutant is lethal in Drosophila This lethality is cell-autonomous, as directed expression of the mutant FicE247G to the fly eye does not kill the fly but rather results in a rough and reduced eye. Lethality and eye phenotypes are rescued by the deAMPylation activity of wild-type Fic. Consistent with Fic acting as a deAMPylation enzyme, its activity was both time- and concentration-dependent. Furthermore, Fic deAMPylation activity was sufficient to suppress the AMPylation activity mediated by the constitutively active FicE247G mutant in Drosophila S2 lysates. Further, we show that the dual enzymatic activity of Fic is, in part, regulated by Fic dimerization, as loss of this dimerization increases AMPylation and reduces deAMPylation of BiP.

SUBMITTER: Casey AK 

PROVIDER: S-EPMC5743091 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Fic-mediated deAMPylation is not dependent on homodimerization and rescues toxic AMPylation in flies.

Casey Amanda K AK   Moehlman Andrew T AT   Zhang Junmei J   Servage Kelly A KA   Krämer Helmut H   Orth Kim K  

The Journal of biological chemistry 20171031 51


Protein chaperones play a critical role in proteostasis. The activity of the major endoplasmic reticulum chaperone BiP (GRP78) is regulated by Fic-mediated AMPylation during resting states. By contrast, during times of stress, BiP is deAMPylated. Here, we show that excessive AMPylation by a constitutively active Fic<sup>E247G</sup> mutant is lethal in <i>Drosophila</i> This lethality is cell-autonomous, as directed expression of the mutant Fic<sup>E247G</sup> to the fly eye does not kill the fly  ...[more]

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