Fic-mediated AMPylation tempers the unfolded protein response during physiological stress

Amanda Casey, Hillery F. Gray, Suneeta Chimalapati, Genaro Hernandez, Andrew T. Moehlman, Nathan Stewart, Hazel A. Fields, Burak Gulen, Kelly A. Servage, Karoliina Stefanius, Aubrie Blevins, Bret M. Evers, Helmut Kramer, Kim Orth

Research output: Contribution to journalArticlepeer-review

Abstract

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

Original languageEnglish (US)
Article numbere2208317119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number32
DOIs
StatePublished - Aug 9 2022

Keywords

  • AMPylation
  • ER stress
  • Fic
  • pancreas
  • unfolded protein response

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Fic-mediated AMPylation tempers the unfolded protein response during physiological stress'. Together they form a unique fingerprint.

Cite this