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