We discovered a bacterial virulence factor from Vibrio parahaemolyticus that mediates the modification of a conserved threonine residue on eukaryotic substrates via a phosphodiester bond with AMP (Yarbrough et al., Science 2009). This modification, called AMPylation, is mediated by a domain called a filamentation induced by cAMP (Fic) domain. We have solved the structure of VopS Fic domain and characterized the kinetics of AMPylation as a direct transfer mechanism. As Fic domains are evolutionarily conserved in metazoans, we demonstrated this post-translational modification in eukaryotes wherein Fic is localized in the ER andreversably AMPylates BiP/GRP78 to maintain ER homeostasis. Further studies demonstrated that adaptation to constant ligh requires Fic-mediated AMPylation of BiP to protect against reversible photoreceptor degeneration.