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1.
EMBO Mol Med ; 15(4): e16434, 2023 04 11.
Article in English | MEDLINE | ID: mdl-36636818

ABSTRACT

Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood. Here we combine single-cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post-transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.


Subject(s)
Interferons , Neural Stem Cells , Mice , Animals , Neural Stem Cells/physiology , Cell Cycle , TOR Serine-Threonine Kinases , Brain
2.
Science ; 371(6524): 57-64, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33384371

ABSTRACT

Accurate assembly of newly synthesized proteins into functional oligomers is crucial for cell activity. In this study, we investigated whether direct interaction of two nascent proteins, emerging from nearby ribosomes (co-co assembly), constitutes a general mechanism for oligomer formation. We used proteome-wide screening to detect nascent chain-connected ribosome pairs and identified hundreds of homomer subunits that co-co assemble in human cells. Interactions are mediated by five major domain classes, among which N-terminal coiled coils are the most prevalent. We were able to reconstitute co-co assembly of nuclear lamin in Escherichia coli, demonstrating that dimer formation is independent of dedicated assembly machineries. Co-co assembly may thus represent an efficient way to limit protein aggregation risks posed by diffusion-driven assembly routes and ensure isoform-specific homomer formation.


Subject(s)
Protein Biosynthesis , Protein Multimerization , Ribosomes/metabolism , Escherichia coli , HEK293 Cells , Humans , Lamins/chemistry , Lamins/metabolism , Protein Domains , Proteome
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