Adaptation to constant light requires Fic-mediated AMPylation of BiP to protect against reversible photoreceptor degeneration

Author:

Moehlman Andrew T1ORCID,Casey Amanda K2,Servage Kelly234,Orth Kim234ORCID,Krämer Helmut15ORCID

Affiliation:

1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States

2. Department of Molecular Biology, UT Southwestern Medical Center, Dallas, United States

3. Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States

4. Howard Hughes Medical Institute, Dallas, United States

5. Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States

Abstract

In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, 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 de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress. After 72 hr of constant light, photoreceptors of fic-null and AMPylation-resistant BiPT366A mutants, but not wild-type flies, display loss of synaptic function, disintegration of rhabdomeres, and excessive activation of ER stress reporters. Strikingly, this phenotype is reversible: photoreceptors regain their structure and function within 72 hr once returned to a standard light:dark cycle. These findings show that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands.

Funder

National Institute of General Medical Sciences

National Eye Institute

Howard Hughes Medical Institute

Welch Foundation

Once Upon A Time Foundation

National Science Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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