Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response
Name
Truttmann-2016-Unrestrained AMPylation targets.pdf
Size
1.39 MB
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Checksum (MD5)
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Author(s)
Truttmann, Matthias C.
Zheng, Xu
Hanke, Leo
Damon, Jadyn R.
Grootveld, Monique
Krakowiak, Joanna
Pincus, David
Ploegh, Hidde
Date Issued
December 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Truttmann, Matthias C. et al. “Unrestrained AMPylation Targets Cytosolic Chaperones and Activates the Heat Shock Response.” Proceedings of the National Academy of Sciences 114, 2 (January 2017): E152–E160 © 2017 National Academy of Sciences
Version
Final published version
Abstract
Protein AMPylation is a conserved posttranslational modification with emerging roles in endoplasmic reticulum homeostasis. However, the range of substrates and cell biological consequences of AMPylation remain poorly defined. We expressed human and Caenorhabditis elegans AMPylation enzymes—huntingtin yeast-interacting protein E (HYPE) and filamentation-induced by cyclic AMP (FIC)-1, respectively—in Saccharomyces cerevisiae, a eukaryote that lacks endogenous protein AMPylation. Expression of HYPE and FIC-1 in yeast induced a strong cytoplasmic Hsf1-mediated heat shock response, accompanied by attenuation of protein translation, massive protein aggregation, growth arrest, and lethality. Overexpression of Ssa2, a cytosolic heat shock protein (Hsp)70, was sufficient to partially rescue growth. In human cell lines, overexpression of active HYPE similarly induced protein aggregation and the HSF1-dependent heat shock response. Excessive AMPylation also abolished HSP70-dependent influenza virus replication. Our findings suggest a mode of Hsp70 inactivation by AMPylation and point toward a role for protein AMPylation in the regulation of cellular protein homeostasis beyond the endoplasmic reticulum.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1619234114
