ABSTRACT
During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the cell’s UPR-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE - alpha-Synuclein (αSyn), a presynaptic protein involved in Parkinson’s disease (PD). Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation in vitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.
Aggregated forms of the presynaptic protein αSyn cause neurotoxicity and induce ER stress in cellular and animal models of Parkinson’s disease.
We have identified αSyn as a novel target for the human Fic protein, HYPE, a key regulator of ER homeostasis.
HYPE adenylylates αSyn and reduces the aggregation of recombinant αSyn
Fic-mediated adenylylation/AMPylation is a possible mechanism by which cells cope with αSyn toxicity.
Graphic Abstract
Footnotes
The authors declare no conflict of interest.
ABBREVIATIONS
- AMP
- :Adenosine monophosphate
- BiP
- :Binding immunoglobulin protein
- BLI
- :Biolayer Inferometry
- ER
- :Endoplasmic reticulum
- FIC
- :Filamentation induced by cAMP
- GFP
- :Green fluorescence protein
- GS-AT
- :Glutamine synthase adenylyltransferase
- HYPE
- :Huntingtin yeast interacting protein E
- LC-MS
- :Liquid chromatography – mass spectrometry
- MAP2
- :Microtubule associated protein 2
- NAC
- :Non-amyloid-beta component of Alzheimer’s disease
- PD
- :Parkinson’s Disease
- PTM
- :Post-translational modification
- SUV
- :Small unilamellar vesicles
- TEM
- :Transmission electron microscopy
- TH
- :Tyrosine hydroxylase
- UPR
- :Unfolded protein response
- WT
- :wild type