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Lipids and proteins shape the physicochemical properties of cellular membranes as a collective, thereby affecting membrane protein function and contributing to organelle identity. Eukaryotic cells face the challenge of maintaining the complex composition of several coexisting organelles. The molecular mechanisms underlying the homeostasis of subcellular membranes and their adaptation during stress are only now starting to emerge. We have studied three membrane property sensors of the endoplasmic reticulum (ER), namely OPI1, MGA2, and IRE1, each controlling a large cellular program impacting on the lipid metabolic network. OPI1 coordinates the production of membrane and storage lipids (Hofbauer et al., 2018), MGA2 regulates the production of unsaturated fatty acids required for membrane biogenesis (Covino et al., 2016; Ballweg et al., 2020), and IRE1 controls the unfolded protein response (UPR) to adjust the abundance and the folding capacity of the ER (Halbleib et al., 2017). Although these three machineries use remarkably distinct sensing mechanisms, they are functionally connected via the ER membrane and cooperate to maintain membrane homeostasis (Covino et al., 2018). Now, it is time to study their cellular role during cellular stress and adaptation by characterizing the molecular composition of isolated organelles from stressed and unstressed cells. Within the framework of the SFB1027, we study how fluctuating signals from the ER membrane can be amplified to mount a robust decision that controls lipid saturation.

Ballweg, S., Sezgin, E., Doktorova, M., Covino, R., Reinhard, J., Wunnicke, D., Hänelt, I., Levental, I., Hummer, G., and Ernst, R. (2020). Regulation of lipid saturation without sensing membrane fluidity. Nat. Commun. 11, 756.

Covino, R., Ballweg, S., Stordeur, C., Michaelis, J.B., Puth, K., Wernig, F., Bahrami, A., Ernst, A.M., Hummer, G., and Ernst, R. (2016). A eukaryotic sensor for membrane lipid saturation. Mol. Cell 63, 49–59.

Covino, R., Hummer, G., and Ernst, R. (2018). Integrated Functions of Membrane Property Sensors and a Hidden Side of the Unfolded Protein Response. Mol. Cell 71, 458–467.

Halbleib, K., Pesek, K., Covino, R., Hofbauer, H.F., Wunnicke, D., Hänelt, I., Hummer, G., and Ernst, R. (2017). Activation of the Unfolded Protein Response by Lipid Bilayer Stress. Mol. Cell 67, 673-684.e8.

Hofbauer, H.F., Gecht, M., Fischer, S.C., Seybert, A., Frangakis, A.S., Stelzer, E.H.K., Covino, R., Hummer, G., and Ernst, R. (2018). The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1. J. Cell Biol. 217, 3109–3126.+

Väth, K., Mattes, C., Reinhard, J., Covino, R., Stumpf, H., Hummer, G., and Ernst, R. (2021). Cysteine cross-linking in native membranes establishes the transmembrane architecture of Ire1. J. Cell Biol. 220, e202011078.