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The nuclear envelope is the signature element of eukaryotes. It separates nucleoplasm from cytoplasm and serves as the protective vessel for the genome. The nuclear envelope combines disparate features: durability with plasticity, selective traffic with mass transport, spatial enclosure with sophisticated signaling. In doing so, it enables cells to protect, decode and regulate their genome. How a single ‘intelligent boundary’ can achieve this multitude of functions remains one of the biggest puzzles in biology. Our goal is to understand the Biology of Boundary Conditions from a mechanistic perspective using the nuclear envelope as a challenging example. This will allow us to understand how it is built, how it breaks, and how to fix it when it is broken.
Three perspectives guide our work on the nuclear envelope: lipids, gates and chromatin. We study how the nuclear envelope regulates its lipid composition and hence material properties, how the boundary opens up via its NPCs and how these gates shape the boundary and interact with the membrane. Notably, the boundary is blurred as the nuclear envelope extends its reach to contact and regulate chromatin. We study how the nuclear envelope affects the nuclear interior, how it initiates the formation of specialized membrane-less compartments and how those affect chromatin function.
Following medical studies in Würzburg, doctoral work at Harvard Medical School, pediatric residency and postdoctoral work in Heidelberg, Alwin became a Junior group leader at the Max Perutz Labs in 2010 and is now the Professor of Mechanistic Cell Biology.
From a cytoplasmic view, the inner nuclear membrane is the most remote territory of the endoplasmic reticulum (ER), both in distance and difficulty of access. To get there, any lipid or protein must pass through the NPCs. Whereas the ER and outer nuclear membrane are highly active in converting nutrients into building blocks for lipids and membranes, the inner nuclear membrane was thought to be metabolically inactive and to receive its entire lipids from the ER via the NPC route. We recently discovered metabolic turnover of lipids at the inner nuclear membrane of budding yeast, and found that the inner nuclear membrane can form lipid droplets that are used for lipid storage (Romanauska & Köhler, Cell 2018). We identified the genetic circuit for the synthesis of nuclear lipid droplets and showed how these organelles participate in gene regulation. This study opens avenues for exploring how inner nuclear membrane lipids signal to the genome and which role the inner nuclear membrane plays in human metabolic diseases.
The assembly of new NPCs is tightly controlled. NPCs are embedded in holes formed by the fusion of the outer and inner nuclear membranes. Inserting a new NPC into an intact nuclear envelope is a fascinating, but poorly understood mechanical problem. Put simply, a hole must be pierced without the balloon popping. Specifically, the inner and outer nuclear membrane have to be bent and fused to open a pore membrane, which has to be stabilized afterwards. In conjunction with this membrane remodeling event, ∼500 nuclear pore proteins have to assemble into a functional NPC to prevent uncontrolled leakage of nuclear or cytoplasmic material. We have discovered a new function for the NPC basket in shaping the nuclear membrane to promote NPC and nuclear envelope integrity (Mészáros et al., Dev Cell, 2015). Future studies aim at understanding how various NPC proteins cooperate to sculpt their membrane environment. We use biochemical reconstitution as a tool to get key insights into what is minimally needed and how mechanisms emerge from component parts.
Tardigrades (also known as water bears or moss piglets) are one of the most resilient animals on our planet: they withstand conditions that would fatal to nearly all other life forms on earth. This includes temperatures from close to absolute zero to about 150°C, pressures six times greater than those found in the deepest ocean trenches, ionizing radiation at doses lethal for a human, and even the vacuum of outer space. Tardigrades can go without food or water for decades, only to rehydrate, forage, and reproduce. They survive this by falling into an enigmatic state called cryptobiosis (hidden life), in which they are neither dead nor alive. We are investigating selected aspects of Tardigrade biology with the support of the Swiss NOMIS Foundation (http://nomisfoundation.ch). We want to understand their outstanding robustness, specifically, how nuclear envelope architecture and function is preserved under extreme conditions.
Related to our interest in gene expression, we are studying the modification of chromatin by ubiquitin. When appended to histones, ubiquitin functions as an important epigenetic switch to regulate multiple steps of transcription. Histone H2B monoubiquitination is mediated by the E2 and E3 enzymes Rad6 and Bre1 (Gallego et al., PNAS 2016). Their activity is counteracted by a deubiquitinase of the SAGA complex (Köhler et al., Cell 2010). We are dissecting the structure and function of this intricate molecular machinery to understand its biology in health and disease. Recently, we have begun to study selected aspects of nuclear protein quality control and its links to nuclear envelope homeostasis.
The Inner Nuclear Membrane Is a Metabolically Active Territory that Generates Nuclear Lipid Droplets.
Romanauska, Anete; Köhler, Alwin
Structural mechanism for the recognition and ubiquitination of a single nucleosome residue by Rad6-Bre1.
Gallego, Laura D; Ghodgaonkar Steger, Medini; Polyansky, Anton A; Schubert, Tobias; Zagrovic, Bojan; Zheng, Ning; Clausen, Tim; Herzog, Franz; Köhler, Alwin
The Nuclear Pore-Associated TREX-2 Complex Employs Mediator to Regulate Gene Expression.
Schneider, Maren; Hellerschmied, Doris; Schubert, Tobias; Amlacher, Stefan; Vinayachandran, Vinesh; Reja, Rohit; Pugh, B Franklin; Clausen, Tim; Köhler, Alwin
DOC Fellowships for Anete Romanauska, Laura Gallego and Jakub Cibulka