Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson's Disease

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Sanyal, Anwesha^1,2,8  Dutta, Sayan³  Camara, Ali¹  Chandran, Aswathy³  Koller, Antonius^4,9  Watson, Ben G.¹  Sengupta, Ranjan¹  Ysselstein, Daniel³  Montenegro, Paola³  Cannons, Jason⁵  Rochet, Jean-Christophe^3,6  Mattoo, Seema^1,7 

[1] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA

[2] Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA

[3] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA

[4] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY USA

[5] Purdue Univ, Sch Hlth Sci, 915 W State St,LILYG 227, W Lafayette, IN 47907 USA

[6] Purdue Univ, Purdue Inst Integrat Neurosci, 915 W State St,LILYG 227, W Lafayette, IN 47907 USA

[7] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, 915 W State St,LILYG 227, W Lafayette, IN 47907 USA

[8] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[9] Northeastern Univ, Barnette Inst, Boston, MA 02115 USA

关键词: Fic;    adenylylation;    AMPylation;    Parkinson's disease;    alpha-synuclein;   

DOI  :  10.1016/j.jmb.2019.04.026

来源: Elsevier

【 摘 要 】

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 unfolded protein response that functions to maintain endoplasmic reticulum (ER) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification called Fic-mediatedadenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an adenosine monophosphate (AMP) to the ER chaperone, BiP, to alter the cell's unfolded protein response-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE alpha-synuclein (alpha Syn), a presynaptic protein involved in Parkinson's disease. Aggregated alpha Syn has been shown to induce ER stress and elicit neurotoxicity in Parkinson's disease models. We show that HYPE adenylylates alpha Syn and reduces phenotypes associated with alpha Syn aggregation invitro, suggesting a possible mechanism by which cells cope with alpha Syn toxicity. (C) 2019 Elsevier Ltd. All rights reserved.

【 授权许可】

Free