Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides

Proceedings of the National Academy of Sciences of the United States of America
Matthias C TruttmannHidde L Ploegh

Abstract

Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn). Expression of a constitutively active C. elegans AMPylase FIC-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Overexpression of FIC-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics...Continue Reading

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Citations

Jun 11, 2020·The Journal of Biological Chemistry· NitikaMatthias C Truttmann
Mar 20, 2019·Journal of Cell Science·Ranjan SenguptaSeema Mattoo
Aug 23, 2020·Experimental Cell Research·Alec M SantiagoKevin A Morano
Jun 11, 2020·Cell Chemical Biology·Stephan A SieberPavel Kielkowski
Apr 11, 2021·The Journal of Biological Chemistry·Andrew W TrumanMehdi Mollapour
May 6, 2021·Open Biology·Bhaskar K Chatterjee, Matthias C Truttmann
Aug 23, 2021·The Journal of Biological Chemistry·Nicholas McCaulMatthias C Truttmann

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Methods Mentioned

BETA
transgenic
filter
fluorescence recovery after photobleaching
protein folding

Software Mentioned

Lifespan

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