Universität zu Köln

Hou, Nicole S., Gutschmidt, Aljona, Choi, Daniel Y., Pather, Keouna, Shi, Xun, Watts, Jennifer L., Hoppe, Thorsten ORCID: 0000-0002-4734-9352 and Taubert, Stefan ORCID: 0000-0002-2432-7257 (2014). Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo. Proc. Natl. Acad. Sci. U. S. A., 111 (22). S. E2271 - 10. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

The Mediator is a conserved transcriptional coregulator complex required for eukaryotic gene expression. In Caenorhabditis elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress responses. mdt-15 loss of function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that worms with mutated or depleted mdt-15 (mdt-15 worms) exhibit decreased membrane phospholipid desaturation, especially in phosphatidylcholine. Accordingly, mdt-15 worms exhibit disturbed endoplasmic reticulum (ER) homeostasis, as indicated by a constitutively activated ER unfolded protein response (UPRER). Activation of this stress response is only partially the consequence of reduced membrane lipid desaturation, implicating other mdt-15-regulated processes in maintaining ER homeostasis. Interestingly, mdt-15 inactivation or depletion of the lipid metabolism enzymes stearoyl-CoA-desaturases (SCD) and S-adenosyl methionine synthetase (sams-1) activates the UPRER without promoting misfolded protein aggregates. Moreover, these worms exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with mutations in UPRER genes, which cause protein misfolding. Therefore, the constitutively activated UPRER in mdt-15, SCD, and sams-1 worms is not the consequence of proteotoxic stress but likely is the direct result of changes in ER membrane fluidity and composition. Together, our data suggest that the UPRER is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hou, Nicole S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutschmidt, Aljona UNSPECIFIED UNSPECIFIED UNSPECIFIED Choi, Daniel Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pather, Keouna UNSPECIFIED UNSPECIFIED UNSPECIFIED Shi, Xun UNSPECIFIED UNSPECIFIED UNSPECIFIED Watts, Jennifer L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED Taubert, Stefan UNSPECIFIED orcid.org/0000-0002-2432-7257 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-435992
DOI:	10.1073/pnas.1318262111
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	111
Number:	22
Page Range:	S. E2271 - 10
Date:	2014
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SATURATED FATTY-ACIDS; INDUCED ER STRESS; CAENORHABDITIS-ELEGANS; C-ELEGANS; RNAI SCREEN; HOMEOSTASIS; PHOSPHOLIPIDS; CARDIOLIPIN; DESATURASE; METABOLISM Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/43599