Large-scale endoplasmic reticulum membrane solidification spatially organizes proteins under thermal or metabolic stress

Mueller, P. M.; Mikolaj, M. R.; Belbaraka, E.; Hartstein, F.; Altinoluk, S.; Perder, B.; Trnka, P.; Welke, R.-W.; Naumann, H.; Taudien, N.; Solimena, M.; Kunz, S.; Levental, I.; Levental, K. R.; Mueller, A.; Ewers, H.; Narayan, K.; Rocks, O.

doi:10.64898/2026.04.09.717431

bioRxiv · 10.64898/2026.04.09.717431

Large-scale endoplasmic reticulum membrane solidification spatially organizes proteins under thermal or metabolic stress

Mueller, P. M.·Mikolaj, M. R.·Belbaraka, E.·Hartstein, F.·Altinoluk, S.·Perder, B.·Trnka, P.·Welke, R.-W.·Naumann, H.·Taudien, N.·Solimena, M.·Kunz, S.·Levental, I.·Levental, K. R.·Mueller, A.·Ewers, H.·Narayan, K.·Rocks, O.

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Abstract

Organelle homeostasis is a key determinant of cellular fitness, yet how cells remodel their membranes in response to environmental change remains unclear. Here, we identify a temperature- and lipid saturation-dependent transformation of endoplasmic reticulum membranes into giant, rigid, multilamellar tubes in cells and in vivo. These rods emerge from demixing of saturated lipids into solid-like domains - a previously unrecognised, large-scale endomembrane phase behaviour, fundamentally distinct from the transient liquid-ordered nanodomains of the plasma membrane. ER-tubulating reticulon-homology proteins are excluded from rods; their segregation drives progressive membrane flattening and ultimately multilayered wrapping. Surfactant-producing alveolar type-II lung cells, enriched in saturated lipids, form rods even at 37{degrees}C, demonstrating that native lipid metabolism can induce this transformation. This spatially organizing lipid-protein domain interplay may tune the ER tubule/sheet balance and provide a homeoviscous mechanism to preserve fluidity in the cholesterol-poor ER under thermal or metabolic stress.

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Mueller, P. M., Mikolaj, M. R., Belbaraka, E., Hartstein, F., Altinoluk, S., Perder, B., Trnka, P., Welke, R.-W., Naumann, H., Taudien, N., Solimena, M., Kunz, S., Levental, I., Levental, K. R., Mueller, A., Ewers, H., Narayan, K., Rocks, O.. 2026-04-12. Large-scale endoplasmic reticulum membrane solidification spatially organizes proteins under thermal or metabolic stress. https://doi.org/10.64898/2026.04.09.717431

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