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Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

Oh, Jang-Hyun and Hyun, Ju-Yeon and Varshavsky, Alexander (2017) Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America, 114 (22). E4370-E4379. ISSN 0027-8424. PMCID PMC5465900. doi:10.1073/pnas.1705898114.

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We found that the heat shock protein 90 (Hsp90) chaperone system of the yeast Saccharomyces cerevisiae is greatly impaired in naa10Δ cells, which lack the NatA N^α-terminal acetylase (Nt-acetylase) and therefore cannot N-terminally acetylate a majority of normally N-terminally acetylated proteins, including Hsp90 and most of its cochaperones. Chk1, a mitotic checkpoint kinase and a client of Hsp90, was degraded relatively slowly in wild-type cells but was rapidly destroyed in naa10Δ cells by the Arg/N-end rule pathway, which recognized a C terminus-proximal degron of Chk1. Diverse proteins (in addition to Chk1) that are shown here to be targeted for degradation by the Arg/N-end rule pathway in naa10Δ cells include Kar4, Tup1, Gpd1, Ste11, and also, remarkably, the main Hsp90 chaperone (Hsc82) itself. Protection of Chk1 by Hsp90 could be overridden not only by ablation of the NatA Nt-acetylase but also by overexpression of the Arg/N-end rule pathway in wild-type cells. Split ubiquitin-binding assays detected interactions between Hsp90 and Chk1 in wild-type cells but not in naa10Δ cells. These and related results revealed a major role of Nt-acetylation in the Hsp90-mediated protein homeostasis, a strong up-regulation of the Arg/N-end rule pathway in the absence of NatA, and showed that a number of Hsp90 clients are previously unknown substrates of the Arg/N-end rule pathway.

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URLURL TypeDescription DOIArticle CentralArticle Information
Oh, Jang-Hyun0000-0002-2053-7468
Hyun, Ju-Yeon0000-0002-5526-9651
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2017 National Academy of Sciences. Contributed by Alexander Varshavsky, April 18, 2017 (sent for review April 10, 2017; reviewed by Avram Hershko and William P. Tansey). Published online before print May 17, 2017. We thank A. Melnykov, I. Printsev, and T. T. M. Vu (California Institute of Technology) for their comments on the manuscript and the present and former members of the A.V. laboratory for their assistance and advice. This work was supported by NIH Grants GM031530 and DK039520 (to A.V.). Author contributions: J.-H.O. and A.V. designed research; J.-H.O. and J.-Y.H. performed research; J.-H.O., J.-Y.H., and A.V. analyzed data; and J.-H.O. and A.V. wrote the paper. Reviewers: A.H., Technion Israel Institute of Technology; and W.P.T., Vanderbilt University School of Medicine. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Subject Keywords:Naa10; Chk1; Ubr1; Ufd4; protein degradation
Issue or Number:22
PubMed Central ID:PMC5465900
Record Number:CaltechAUTHORS:20170518-073119611
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Official Citation:Jang-Hyun Oh, Ju-Yeon Hyun, and Alexander Varshavsky Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway PNAS 2017 114 (22) E4370-E4379; published ahead of print May 17, 2017, doi:10.1073/pnas.1705898114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:77547
Deposited By: Tony Diaz
Deposited On:18 May 2017 15:58
Last Modified:28 Mar 2022 21:50

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