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Regulation of the Unfolded Protein Response by Fic‐mediated Adenylylation/AMPylation
Author(s) -
Mattoo Seema,
Sanyal Anwesha
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.652.8
Subject(s) - adenylylation , unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , chemistry , biology , biochemistry , enzyme , biosynthesis
Maintenance of ER (endoplasmic reticulum) homeostasis is a critical aspect of determining cell fate, and requires a properly functioning unfolded protein response (UPR) to combat such stress. We have discovered a hitherto unknown role for adenylylation/AMPylation, a post‐translational modification that involves the covalent attachment of an adenosine monophosphate (AMP) to the target protein, 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 reaction. A single Fic protein, called HYPE (Huntingtin yeast interacting protein), exists in humans. We reported that the ER molecular chaperone, BiP, is a target of HYPE‐mediated adenylylation. BiP serves as a sentinel for activating UPR and maintaining ER homeostasis by monitoring protein folding in cells. Our data indicate that HYPE localizes to the ER lumen where it interacts with BiP and adenylylates it, to alter BiP's ATPase activity in vitro . Further, HYPE expression increases upon induction of UPR stress. Accordingly, we demonstrated that cells knocked down for HYPE are unable to mount an appropriate UPR and are more susceptible to stress induced cell death. As such, HYPE represents a new player in UPR signaling. Here, we assess the cellular consequences of BiP adenylylation during UPR progression and describe the structural and kinetic parameters that govern the HYPE‐BiP interaction. Support or Funding Information This work was supported by funding from 1) an Indiana CTSI (Clinical and Translational Sciences Institute) Core Pilot Grant, 2) a Showalter Research Trust Award, 3) an American Cancer Society (ACS) Institutional Grant, and 4) the National Institute Of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number R01GM100092.