Cellular compartment | EPFL Graph Search

Cellular compartments in cell biology comprise all of the closed parts within the cytosol of a eukaryotic cell, usually surrounded by a single or double lipid layer membrane. These compartments are often, but not always, defined as membrane-bound organelles. The formation of cellular compartments is called compartmentalization. Both organelles, the mitochondria and chloroplasts (in photosynthetic organisms), are compartments that are believed to be of endosymbiotic origin. Other compartments such as peroxisomes, lysosomes, the endoplasmic reticulum, the cell nucleus or the Golgi apparatus are not of endosymbiotic origin. Smaller elements like vesicles, and sometimes even microtubules can also be counted as compartments. It was thought that compartmentalization is not found in prokaryotic cells., but the discovery of carboxysomes and many other metabolosomes revealed that prokaryotic cells are capable of making compartmentalized structures, albeit these are in most cases not surroun

Biological nanopores for single-molecule sensing

Chan Cao, Matteo Dal Peraro, Simon Finn Mayer

Evolution has found countless ways to transport material across cells and cellular compartments separated by membranes. Protein assemblies are the cornerstone for the formation of channels and pores that enable this regulated passage of molecules in and out of cells, contributing to maintaining most of the fundamental processes that sustain living organisms. As in several other occasions, we have borrowed from the natural properties of these biological systems to push technology forward and have been able to hijack these nano-scale proteinaceous pores to learn about the physical and chemical features of molecules passing through them. Today, a large repertoire of biological pores is exploited as molecular sensors for characterizing biomolecules that are relevant for the advancement of life sciences and application to medicine. Although the technology has quickly matured to enable nucleic acid sensing with transformative implications for genomics, biological pores stand as some of the most promising candidates to drive the next developments in single-molecule proteomics.

2022

Exploring the mechanisms governing nuclear cGAS localization and activity

Marilena Wischnewski

Recognition of pathogen-derived molecules through germline-encoded receptors is a fundamental principle of innate immunity. Pattern recognition receptors detect specific intracellular danger signals to trigger potent immune responses. The DNA sensor cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA derived from viruses and microbes in the cytoplasm. However, due to its ability to recognize DNA independent of sequence, aberrant detection of self-DNA in various settings can lead to autoinflammatory diseases. Under physiological conditions, genomic DNA is sequestered in the nucleus and shielded from cytosolic molecules by the nuclear envelope (NE). Nevertheless, cGAS gains access to the nuclear compartment in some instances, and the mechanisms controlling its activity on genomic DNA are not fully known.In this study, we investigate the regulation of nuclear cGAS localization and activity in different contexts. We first describe how cGAS activity against nuclear DNA is restricted in instances of spontaneous loss of nucleo-cytoplasmic compartmentalization. Upon NE rupture, cGAS enters the nucleus, but is prevented from activation by Barrier-to-autointegration factor 1 (BAF). BAF dynamically competes with cGAS for DNA binding, thereby preventing the formation of stable cGAS-DNA complexes and cGAS enzymatic activity. We thus identify a cellular safeguard mechanism, beyond physical separation, that restricts cGAS activity against genomic self-DNA.In addition, we investigate cGAS activation in conditions associated with a disrupted NE. Instability of the NE is a hallmark of laminopathies, diseases of the nuclear lamina that can manifest in premature aging phenotypes. While we find no contribution of basal cGAS signaling to the pathogenesis of two different progeria syndromes, we detect a decreased capacity to respond to DNA challenge on the cellular level, suggesting that cGAS may be sequestered inside the nucleus in these cells.Lastly, because cGAS is increasingly recognized to reside inside the nucleus at steady state, we delineate cGAS nuclear localization in time and space. In cycling cells, nuclear cGAS levels oscillate with the cell cycle and are highest after mitosis followed by a sharp decrease in G1 phase. We report that cGAS is not exported during G1, but rather subjected to degradation inside the nucleus by the nuclear proteasome. Moreover, we establish a technique to study potential interaction partners of nuclear cGAS, which opens up intriguing possibilities for further investigation.Together, our findings contribute to a better understanding of the regulatory processes that govern nuclear cGAS localization and activity, and will help to uncover potential disease-causing aberrations in the future.

EPFL2022

Modulation of Subcellular Redox Homeostasis with Trialkylphosphines

Jade Noémie Nam Nguyen

Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced (GSH) and oxidized (GSSG) glutathione. In eukaryotic cells, this ratio is different in each cell compartment. There is a lack of chemical probes able to modulate GSH/GSSG to study the impact of redox stress in an organelle specific manner. Here, we highlight the importance of trialkylphosphines to induce reductive stress and how it can be targeted to a specific organelle. Our probe is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that the induced stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.

SWISS CHEMICAL SOC2022

Exploring the mechanisms governing nuclear cGAS localization and activity

Marilena Wischnewski

EPFL2022