Principal Investigator


P21  Robert Ernst

Group Leader


Professor for Molecular Biology since 2017

University of Saarland
School of Medicine
Institute of Biochemistry
Kirrberger Strasse
66421 Homburg (Saar)

Former member of
Institute of Biochemistry
Goethe University Frankfurt a.M.

Project funding
01/2014 - 06/2018

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P21 Activation mechanism of the unfolded protein response by lipid bilayer stress

Biological membranes are complex assemblies of proteins and lipids and numerous essential signaling events occur at the surface of organelles. Consequently, organelles must maintain their surface properties and composition. The unfolded protein response (UPR) mediated by Ire1 is a homeostatic program regulating the expression of more than 5% of the genes encoded by Saccharomcyes cerevisiae. This pathway is conserved among all eukaryotes and regulates the protein folding capacity of the endoplasmic reticulum (ER), the ER-associated degradation, and ER abundance. In the past decade it became evident that Ire1 is activated not only by unfolded proteins, but also by aberrant lipid compositions. The molecular mechanism of UPR activation by lipid bilayer stress, however, remained obscure. We are studying the molecular mechanism of Ire1-activation by lipid bilayer stress and characterize the structural features underlying this process.


Upon membrane stress the nuclear envelope forms membrane extrusions and whorl-like structures (white arrows). Electron micrographs of Saccharomyces cerevisiae cells show that only the other membrane of the nucleus (N) forms these ER-membrane whorls.




Halbleib R, Pesek K, Covino R, Hofbauer HF, Wunnicke D, Hänelt I, Hummer G, Ernst R (2017) Activation of the unfolded protein response by lipid bilayer stress. Mol Cell 67, 673-685.

Ernst R, Ejsing C, Antonny B (2016) Homeoviscous adaptation and the regulation of membrane lipids. J Mol Biol 428, 4776-91.

Covino C, Ballweg S, Stordeur C, Michaelis JB, Pesek K, Wernig F, Bahrami A, Ernst AM, Hummer G, Ernst R (2016) A eukaryotic sensor for membrane lipid saturation. Molecular Cell 63, 49-59.

Puth K, Hofbauer HF, Saenz JP, Ernst R (2015) Homeostatic control of biological membranes by dedicated lipid and membrane packing sensors. Biol Chem 396, 1043-58.

Mehla J, Ernst R, Moore R, Wakschlag A, Marquis MK, Ambudkar SV, Golin J (2014) Evidence for a Molecular Diode-based Mechanism in a Multispecific ATP-binding cassette (ABC) Exporter: Ser-1368 as a gatekeeping residue in the yeast multidrug transporter Pdr5. J Biol Chem 289, 26597-606.

Stordeur C, Puth K, Saenz JP, Ernst R (2014). Crosstalk of lipid and protein homeostasis to maintain membrane function. Biol Chem 395, 313-26.

Surma MA, Klose C, Peng D, Shales M, Mrejen C, Stefanko A, Braberg H, Gordon ED, Vorkel D, Ejsing CS, Farese RF Jr, Simons K, Krogan NJ*, Ernst R* (2013) A lipid E-MAP identified Ubx2 as a critical regulator of lipid saturation and lipid bilayer stress. Mol Cell 51, 519-30.

Ernst R*, Claessen JH*, Mueller B, Sanyal S, Spooner E, van der Veen AG, Kirak O, Schlieker CD, Weihofen WA, Ploegh HL (2011) Enzymatic blockade of the ubiquitin-proteasome pathway. PLoS Biology 8, e1000605.

*equal contribution





Schwalbe (P13), Glaubitz (P06), Hummer (P25), Hänelt (P22), Heilemann (P20)