Lysine trimethylation regulates 78-kDa glucose-regulated protein proteostasis during endoplasmic reticulum stress

Jonas Sieber, Nicolas Wieder, Mauricio Ostrosky-Frid, Moran Dvela-Levitt, Ozan Aygün, Namrata D. Udeshi, Steven A. Carr, Anna Greka

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The up-regulation of chaperones such as the 78-kDa glucoseregulated protein (GRP78, also referred to as BiP or HSPA5) is part of the adaptive cellular response to endoplasmic reticulum (ER) stress. GRP78 is widely used as a marker of the unfolded protein response, associated with sustained ER stress. Here we report the discovery of a proteostatic mechanism involving GRP78 trimethylation in the context of ER stress. Using mass spectrometry-based proteomics, we identified two GRP78 fractions, one homeostatic and one induced by ER stress. ER stress leads to de novo biosynthesis of non-trimethylated GRP78, whereas homeostatic, METTL21A-dependent lysine 585- trimethylated GRP78 is reduced. This proteostatic mechanism, dependent on the posttranslational modification of GRP78, allows cells to differentially regulate specific protein abundance during cellular stress.

Original languageEnglish
Pages (from-to)18878-18885
Number of pages8
JournalJournal of Biological Chemistry
Issue number46
StatePublished - 17 Nov 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.


A. G. declares consultation services for Bristol Myers Squibb, Third Rock Ven-tures, and Goldfinch Bio. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains supplemental Fig. 1 and Table 1. 1 Both authors contributed equally to this work. 2Supported by Swiss National Science Foundation Fellowships PBBSP3-144160 and P300P3-151739. 3 Supported by Deutsche Forschungsgesellschaft Fellowship WI 4612/1-1. 4 Supported by a Broad-ISF postdoctoral fellowship. 5 Supported by National Institutes of Health Grants DK099465 and DK095045. To whom correspondence should be addressed: Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine, 4 Black-fan Circle, Boston, MA 02115. Tel.: 617-525-5939; Fax: 617-525-5965; E-mail: [email protected] or [email protected]. 6The abbreviations used are: ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress; UPR, unfolded protein response; TMT, tandem mass tag.

FundersFunder number
National Institutes of HealthDK099465, DK095045
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungP300P3-151739, WI 4612/1-1, PBBSP3-144160


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