The nuclear pore complex is a highly selective gateway that regulates molecular traffic between the nucleus and cytoplasm. But its role goes further. NPCs are also membrane-remodeling machines: they bend, fuse, and stabilize the double membrane of the nuclear envelope to create large pores – remarkably, without compromising nuclear integrity. How they achieve this remains one of cell biology’s enduring mysteries.
With support from the ERC, Alwin Köhler and his team aim to uncover the physical and biochemical principles that enable NPCs to reshape the nuclear envelope. A key focus will be the role of nuclear lipid metabolism – specifically, how cells adjust the lipid composition of the nuclear envelope to permit sculpting by NPCs. Although still poorly understood, this process is increasingly recognized as central to nuclear organization and stability.
“We’ve made great progress in understanding the structure of nuclear pore complexes,” Alwin Köhler says. “But we still don’t know how they assemble on membranes in living cells – how proteins and lipids work together to build such a large, intricate structure without tearing the nuclear envelope.”
To investigate this, the team will reconstitute NPC assembly on artificial membranes, allowing them to visualize how nucleoporins bend and fuse lipid bilayers. These experiments will be paired with systematic profiling of the lipid environment and key metabolic enzymes at the inner nuclear membrane – a surprisingly uncharted region of the cell.
By integrating structural biology, spatially resolved lipidomics, and developing new tools to reconstitute and visualize NPC assembly, the project aims to uncover general principles of how cells build and maintain complex, membrane-spanning machines. NPCs are among the most iconic molecular assemblies in eukaryotic cells. Their dysfunction has been linked to ageing, viral infection, and cancer. Understanding how they form – and fail – could open new avenues in biomedical research.
This €2.5 million ERC Advanced Grant marks the latest milestone in Alwin Köhler’s long-standing investigation of nuclear architecture. He is Professor of Molecular Biology at both the Medical University of Vienna and the University of Vienna, member of EMBO and the Austrian Academy of Sciences, a NOMIS researcher, and a Moore Distinguished Scholar at the California Institute of Technology (Caltech). His lab has advanced our understanding of nuclear structure and function – from NPC biology and chromatin organization to, more recently, how cells cope with extreme stress in organisms like tardigrades. The ERC project builds on this trajectory, broadening its scope to explore how physical forces, lipids, and protein assemblies interact to shape one of life’s most essential structures.
As Alwin Köhler puts it: “We’re asking how cells manage to build nuclear pores – in the right place, at the right time, with the right material. It’s a simple question, but answering it touches on some of the deepest principles of cellular organization.”