A Novel Link Between Fic (Filamentation induced by cAMP)-mediated Adenylylation/AMPylation and the Unfolded Protein Response [Cell Biology]

January 19th, 2015 by Sanyal, A., Chen, A. J., Nakayasu, E. S., Lazar, C. S., Zbornik, E. A., Worby, C. A., Koller, A., Mattoo, S.

Maintenance of ER (endoplasmic reticulum) homeostasis is a critical aspect of determining cell fate and requires a properly functioning unfolded protein response (UPR). We have discovered a hitherto unknown role of a post-translational modification termed adenylylation/AMPylation in regulating signal transduction events during UPR induction. A family of enzymes, defined by the presence of a Fic (filamentation induced by cAMP) domain, catalyzes this adenylylation reaction. The human genome encodes a single Fic protein, called HYPE (Huntingtin yeast interacting protein E), with adenylyltransferase activity but unknown physiological target(s). Here, we demonstrate that HYPE localizes to the lumen of the endoplasmic reticulum via its hydrophobic N-terminus, and adenylylates the ER molecular chaperone, BiP, at Ser365 and Thr366. BiP functions as a sentinel for protein misfolding and maintains ER homeostasis. We find that adenylylation enhances the ATPase activity of BiP, which is required for refolding misfolded proteins while coping with ER stress. Accordingly, HYPE expression levels increase upon stress. Further, siRNA-mediated knockdown of HYPE prevents the induction of an unfolded protein response. We, thus, identify HYPE as a new UPR regulator and provide the first functional data for Fic-mediated adenylylation in mammalian signaling.