Genetic Analysis of Fic-Mediated BiP AMPylation in Photoreceptors

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2019-04-10

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Moehlman, Andrew Terry

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Abstract

In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. The Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or deAMPylation of BiP, the major ER chaperone. This work elucidates a critical role of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to constant light-induced stress. In response to extended light exposure, flies mutant for fic display loss of synaptic function and disintegration of rhabdomeres, closely stacked plasma membrane microvilli that house the proteins of the phototransduction cascade. These phenotypes are replicated in BiP mutants lacking the Thr366 AMPylation site. Strikingly, these degeneration-like phenotypes are reversible: photoreceptors in both fic and bip mutants regain their structure and function within 72 hours once returned to a standard light:dark cycle. In fic mutants, these phenotypes are preceded by a dysregulation of the IREI and PERK-mediated ER stress responses detected with specific reporters. These findings indicate that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands, and that this process may require proper activation of the Unfolded Protein Response. Furthermore, I have helped identify multiple cell membrane transporters involved in synaptic signaling between photoreceptors and lamina neurons. These transporters are involved directly and indirectly in the recycling of the neurotransmitter histamine in the synaptic cleft.

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