skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response

; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1414301
Grant/Contract Number:
DEAC02- 06CH11357
Resource Type:
Journal Article: Published Article
Journal Name:
Additional Journal Information:
Journal Volume: 168; Journal Issue: 6; Related Information: CHORUS Timestamp: 2018-03-08 21:16:29; Journal ID: ISSN 0092-8674
Country of Publication:
United States

Citation Formats

Riback, Joshua A., Katanski, Christopher D., Kear-Scott, Jamie L., Pilipenko, Evgeny V., Rojek, Alexandra E., Sosnick, Tobin R., and Drummond, D. Allan. Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response. United States: N. p., 2017. Web. doi:10.1016/j.cell.2017.02.027.
Riback, Joshua A., Katanski, Christopher D., Kear-Scott, Jamie L., Pilipenko, Evgeny V., Rojek, Alexandra E., Sosnick, Tobin R., & Drummond, D. Allan. Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response. United States. doi:10.1016/j.cell.2017.02.027.
Riback, Joshua A., Katanski, Christopher D., Kear-Scott, Jamie L., Pilipenko, Evgeny V., Rojek, Alexandra E., Sosnick, Tobin R., and Drummond, D. Allan. Wed . "Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response". United States. doi:10.1016/j.cell.2017.02.027.
title = {Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response},
author = {Riback, Joshua A. and Katanski, Christopher D. and Kear-Scott, Jamie L. and Pilipenko, Evgeny V. and Rojek, Alexandra E. and Sosnick, Tobin R. and Drummond, D. Allan},
abstractNote = {},
doi = {10.1016/j.cell.2017.02.027},
journal = {Cell},
number = 6,
volume = 168,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2017},
month = {Wed Mar 01 00:00:00 EST 2017}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.cell.2017.02.027

Citation Metrics:
Cited by: 22works
Citation information provided by
Web of Science

Save / Share:
  • In eukaryotic cells, diverse stresses trigger coalescence of RNA-binding proteins into stress granules. In vitro, stress-granule-associated proteins can demix to form liquids, hydrogels, and other assemblies lacking fixed stoichiometry. Observing these phenomena has generally required conditions far removed from physiological stresses. We show that poly(A)-binding protein (Pab1 in yeast), a defining marker of stress granules, phase separates and forms hydrogels in vitro upon exposure to physiological stress conditions. Other RNA-binding proteins depend upon low-complexity regions (LCRs) or RNA for phase separation, whereas Pab1’s LCR is not required for demixing, and RNA inhibits it. Based on unique evolutionary patterns, we createmore » LCR mutations, which systematically tune its biophysical properties and Pab1 phase separation in vitro and in vivo. Mutations that impede phase separation reduce organism fitness during prolonged stress. Poly(A)-binding protein thus acts as a physiological stress sensor, exploiting phase separation to precisely mark stress onset, a broadly generalizable mechanism.« less
  • Cited by 22
  • Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizablemore » features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.« less
  • Research highlights: {yields} Lipid bilayers have been imaged by atomic force microscopy (AFM). {yields} At pH 5 phase separation occurs in lipid bilayers containing mixed acyl chains. {yields} Phase separation does not occur when lipids have only unsaturated chains. {yields} Phase separation might drive protein clustering during endocytosis. -- Abstract: Endocytosis involves the capture of membrane from the cell surface in the form of vesicles, which become rapidly acidified to about pH 5. Here we show using atomic force microscopy (AFM) imaging that this degree of acidification triggers phase separation in lipid bilayers containing mixed acyl chains (e.g. palmitoyl/oleoyl) ormore » complex mixtures (e.g. total brain extract) but not in bilayers containing only lipids with unsaturated chains (e.g. dioleoyl). Since mixed-chain lipids are major constituents of the outer leaflet of the plasma membrane, the type of phase separation reported here might support protein clustering and signaling during endocytosis.« less
  • Highlights: •GCN1 is required for mammalian and yeast GCN2 function in a variety of conditions. •Mammalian IMPACT competes with GCN2 for GCN1 binding. •IMPACT and its yeast counterpart YIH1 downregulate GCN1-dependent GCN2 activation. -- Abstract: In response to a range of environmental stresses, phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2α) represses general protein synthesis coincident with increased translation of specific mRNAs, such as those encoding the transcription activators GCN4 and ATF4. The eIF2α kinase GCN2 is activated by amino acid starvation by a mechanism involving GCN2 binding to an activator protein GCN1, along with associationmore » with uncharged tRNA that accumulates during nutrient deprivation. We previously showed that mammalian IMPACT and its yeast ortholog YIH1 bind to GCN1, thereby preventing GCN1 association with GCN2 and stimulation of this eIF2α kinase during amino acid depletion. GCN2 activity is also enhanced by other stresses, including proteasome inhibition, UV irradiation and lack of glucose. Here, we provide evidence that IMPACT affects directly and specifically the activation of GCN2 under these stress conditions in mammalian cells. We show that activation of mammalian GCN2 requires its interaction with GCN1 and that IMPACT promotes the dissolution of the GCN2–GCN1 complex. To a similar extent as the overexpression of YIH1, overexpression of IMPACT in yeast cells inhibited growth under all stress conditions that require GCN2 and GCN1 for cell survival, including exposure to acetic acid, high levels of NaCl, H{sub 2}O{sub 2} or benomyl. This study extends our understanding of the roles played by GCN1 in GCN2 activation induced by a variety of stress arrangements and suggests that IMPACT and YIH1 use similar mechanisms for regulating this eIF2α kinase.« less