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J Biol Chem. 2015 Mar 27;290(13):8482-99. doi: 10.1074/jbc.M114.618348. Epub 2015 Jan 19.

A novel link between Fic (filamentation induced by cAMP)-mediated adenylylation/AMPylation and the unfolded protein response.

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From the Department of Biological Sciences and.
Bindley Biosciences Center, Purdue University, West Lafayette, Indiana 47907.
the Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, and.
the Department of Pathology, Stony Brook University, Stony Brook, New York 11794.
From the Department of Biological Sciences and


The maintenance of endoplasmic reticulum (ER) homeostasis is a critical aspect of determining cell fate and requires a properly functioning unfolded protein response (UPR). We have discovered a previously 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 Ser-365 and Thr-366. BiP functions as a sentinel for protein misfolding and maintains ER homeostasis. We found that adenylylation enhances BiP's ATPase activity, which is required for refolding misfolded proteins while coping with ER stress. Accordingly, HYPE expression levels increase upon stress. Furthermore, siRNA-mediated knockdown of HYPE prevents the induction of an unfolded protein response. Thus, we identify HYPE as a new UPR regulator and provide the first functional data for Fic-mediated adenylylation in mammalian signaling.


AMP; AMPylation; Adenylylation; Apoptosis; BiP; Filamentation Induced by cAMP; HYPE/FicD; Post-translational Modification; Signaling; Unfolded Protein Response (UPR)

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